NCBI Conserved Domain Search

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 117.46 E-value: 1.25e-33

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720398219  47 HTFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTCI 101
Cdd:cd22613     1 HSFCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTCI 55

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 105.86 E-value: 3.27e-29

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720398219 117 RPDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKICE 172
Cdd:cd22614     1 KPDFCFLEEDPGICRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTCE 56

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 101.60 E-value: 1.34e-27

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 223 PWCLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22615     2 SFCLSPKDEGLCSASVTRYYYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 85.77 E-value: 1.33e-21

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 224 WCLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:pfam00014   1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 53

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 84.62 E-value: 3.50e-21

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 120 FCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:pfam00014   1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 83.46 E-value: 9.01e-21

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:pfam00014   1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 81.44 E-value: 5.47e-20

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd00109     1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 81.06 E-value: 6.33e-20

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd00109     1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 80.00 E-value: 1.67e-19

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                   ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219   48 TFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:smart00131   1 DVCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 80.00 E-value: 2.10e-19

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                   ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219  223 PWCLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:smart00131   1 DVCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 79.51 E-value: 2.73e-19

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd00109     1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 79.65 E-value: 2.99e-19

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219 118 PDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22608     1 PKFCYLPADPGPCKAYIPRFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 54

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 79.23 E-value: 3.83e-19

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219  119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:smart00131   1 DVCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 79.32 E-value: 4.01e-19

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 120 FCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22613     3 FCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

Kunitz domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438660 Cd Length: 54 Bit Score: 77.81 E-value: 1.27e-18

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22617     4 CREVPDEGPCRALITRYFYNMTSMRCEEFTYGGCYGNGNNFRDKSSCISAC 54

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438637 Cd Length: 56 Bit Score: 77.36 E-value: 1.87e-18

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219  47 HTFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22594     2 PKFCELPADPGPCNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 75.74 E-value: 7.03e-18

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22616     5 CLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 74.26 E-value: 2.36e-17

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                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22608     3 FCYLPADPGPCKAYIPRFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 54

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 74.43 E-value: 2.67e-17

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720398219 116 ERPDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKICENPV 175
Cdd:cd22599     1 QRNGICRLPADEGICRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKACGAPE 60

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438637 Cd Length: 56 Bit Score: 73.89 E-value: 4.44e-17

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720398219 117 RPDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22594     1 RPKFCELPADPGPCNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 72.72 E-value: 8.77e-17

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22608     4 CYLPADPGPCKAYIPRFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 54

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 72.34 E-value: 1.45e-16

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219  48 TFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22614     3 DFCFLEEDPGICRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTC 55

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 72.51 E-value: 1.51e-16

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTCI 101
Cdd:cd22599     5 ICRLPADEGICRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKACG 57

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 70.88 E-value: 4.28e-16

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22638     1 CTLKPETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Kunitz-type serine protease inhibitor 6 (BmTI-6), A (BmTI-A), and similar proteins; This group includes Kunitz-type serine protease inhibitors 6 (BmTI-6) and A (BmTI-A), both of which inhibit bovine trypsin, bovine chymotrypsin, human plasmin, human plasma kallikrein and human neutrophil elastase, but not bovine thrombin, human factor Xa or porcine pancreatic kallikrein. They may play a role in blocking blood coagulation during the larvae fixation on cattle. This subfamily also includes Rhipicephalus microplus protease inhibitor carrapatin. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438647 [Multi-domain] Cd Length: 56 Bit Score: 70.94 E-value: 5.12e-16

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219  48 TFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22604     4 KQCSPTADSGPCFAYFPMWWYNVKTGQCEEFIYGGCQGNDNRYETEEECEKTC 56

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 70.54 E-value: 7.26e-16

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22603     1 EDCLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 69.60 E-value: 1.15e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 121 CFLEEDPG-LCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22635     1 CLLDKDAGtVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438667 Cd Length: 61 Bit Score: 69.85 E-value: 1.30e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:cd22624     2 CTEPPVTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETCS 53

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438675 Cd Length: 55 Bit Score: 69.77 E-value: 1.37e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22632     3 LCQLPPARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTC 54

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 69.57 E-value: 1.39e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22616     5 CLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438638 Cd Length: 56 Bit Score: 69.01 E-value: 2.19e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219  48 TFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTCI 101
Cdd:cd22595     2 KFCKLPVRPGPCKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTCV 55

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 68.83 E-value: 2.65e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSG-LCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22635     1 CLLDKDAGtVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438637 Cd Length: 56 Bit Score: 68.11 E-value: 4.58e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 223 PWCLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22594     3 KFCELPADPGPCNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 68.33 E-value: 4.61e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219 118 PDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22633     2 NSICLLPKDVGGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 67.66 E-value: 7.21e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22596     1 DSCKLPPDAGPCFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 67.46 E-value: 8.52e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22603     2 DCLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 67.56 E-value: 9.48e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 223 PWCLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22633     3 SICLLPKDVGGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438677 Cd Length: 57 Bit Score: 67.54 E-value: 9.61e-15

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219  48 TFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22634     5 PHSLGGGDGISCFAYIPSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 67.09 E-value: 1.14e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22609     1 FCLEPKVVGVCKASMTRYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 52

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 67.09 E-value: 1.18e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 120 FCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22609     1 FCLEPKVVGVCKASMTRYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 52

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438666 Cd Length: 59 Bit Score: 66.41 E-value: 2.06e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKICEN 173
Cdd:cd22623     4 LYCLAPKKVGPCRGSFPRWHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSACRG 58

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438654 Cd Length: 57 Bit Score: 66.27 E-value: 2.55e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKICENP 174
Cdd:cd22611     1 DVCSLPKESGPCMAYFPRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNICKKK 56

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438675 Cd Length: 55 Bit Score: 65.92 E-value: 2.98e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720398219 118 PDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKICE 172
Cdd:cd22632     1 PSLCQLPPARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTCK 55

Kunitz domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438660 Cd Length: 54 Bit Score: 65.48 E-value: 4.33e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219 118 PDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22617     1 PKVCREVPDEGPCRALITRYFYNMTSMRCEEFTYGGCYGNGNNFRDKSSCISAC 54

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 65.53 E-value: 5.02e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22603     3 CLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

second Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the second Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438645 Cd Length: 51 Bit Score: 65.25 E-value: 5.49e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22602     1 CSLPSKVGPCRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 65.39 E-value: 5.54e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219 118 PDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22615     1 PSFCLSPKDEGLCSASVTRYYYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 64.55 E-value: 8.46e-14

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22593     1 CSLPLDEGSGNSSLTRWYYDPKKGQCKPFTYKGKGGNENNFLTKEDCEETC 51

Kunitz-type domain 2 (K2) of Ixolaris, and similar proteins; This model includes the second Kunitz-type domain (K2) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. This model contains K2, an extraordinarily dynamic domain that encompasses several residues involved in FX binding. Its backbone plasticity is critical for ixolaris biological activity. This domain contains 2 disulfide bonds instead of the 3 typical of Kunitz domain proteins.

Pssm-ID: 438669 Cd Length: 51 Bit Score: 64.40 E-value: 1.05e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22626     1 CSLELDYGVGKAYIPRWYFNTSNARCEMFIFGGIGGNKNNFETLEECKKTC 51

first Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the first Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438644 Cd Length: 55 Bit Score: 64.45 E-value: 1.23e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720398219  47 HTFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTCI 101
Cdd:cd22601     1 IDVCDLPADRGPCTAYIPRWFYNKTTKKCEKFVYGGCQGNKNRFETKDDCLANCG 55

Kunitz-type serine protease inhibitor 6 (BmTI-6), A (BmTI-A), and similar proteins; This group includes Kunitz-type serine protease inhibitors 6 (BmTI-6) and A (BmTI-A), both of which inhibit bovine trypsin, bovine chymotrypsin, human plasmin, human plasma kallikrein and human neutrophil elastase, but not bovine thrombin, human factor Xa or porcine pancreatic kallikrein. They may play a role in blocking blood coagulation during the larvae fixation on cattle. This subfamily also includes Rhipicephalus microplus protease inhibitor carrapatin. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438647 [Multi-domain] Cd Length: 56 Bit Score: 64.39 E-value: 1.24e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22604     4 KQCSPTADSGPCFAYFPMWWYNVKTGQCEEFIYGGCQGNDNRYETEEECEKTC 56

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 64.16 E-value: 1.25e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22630     1 DACSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 53

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 63.92 E-value: 1.49e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22606     2 CSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

first Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the first Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438644 Cd Length: 55 Bit Score: 64.06 E-value: 1.61e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22601     2 DVCDLPADRGPCTAYIPRWFYNKTTKKCEKFVYGGCQGNKNRFETKDDCLANC 54

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 63.92 E-value: 1.65e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22606     2 CSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 63.93 E-value: 1.71e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22629     1 DICKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 63.81 E-value: 1.71e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:cd22596     3 CKLPPDAGPCFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTCR 54

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438643 Cd Length: 54 Bit Score: 63.99 E-value: 1.73e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKICEN 173
Cdd:cd22600     2 CKPAAESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELACLR 54

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 63.82 E-value: 1.77e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22592     1 FCLEPPYTGPCKARIIRYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 52

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 63.78 E-value: 2.20e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTCIP 102
Cdd:cd22630     2 ACSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALCVK 55

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 63.56 E-value: 2.22e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22638     1 CTLKPETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 63.41 E-value: 2.47e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22616     5 CLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438666 Cd Length: 59 Bit Score: 63.72 E-value: 2.60e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:cd22623     6 CLAPKKVGPCRGSFPRWHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSACR 57

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 63.04 E-value: 3.80e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22592     2 CLEPPYTGPCKARIIRYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 52

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 62.68 E-value: 4.16e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22628     1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438677 Cd Length: 57 Bit Score: 62.91 E-value: 4.26e-13

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1720398219 126 DPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22634    12 DGISCFAYIPSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 62.94 E-value: 4.74e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720398219  46 LHTFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22633     1 INSICLLPKDVGGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 62.76 E-value: 5.01e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22606     2 CSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 62.59 E-value: 5.61e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTCI 101
Cdd:cd22639     1 CSLPKDRGPCRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVCV 52

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438643 Cd Length: 54 Bit Score: 62.45 E-value: 5.91e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTCIP 102
Cdd:cd22600     2 CKPAAESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELACLR 54

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438643 Cd Length: 54 Bit Score: 62.06 E-value: 7.30e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:cd22600     2 CKPAAESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELACL 53

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 62.11 E-value: 8.72e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:cd22599     6 CRLPADEGICRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKACG 57

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438665 Cd Length: 53 Bit Score: 61.99 E-value: 8.98e-13

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22622     2 YCAAPRVTGPCRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 61.54 E-value: 1.11e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22615     3 FCLSPKDEGLCSASVTRYYYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 61.69 E-value: 1.17e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22609     2 CLEPKVVGVCKASMTRYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 52

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438667 Cd Length: 61 Bit Score: 61.38 E-value: 1.67e-12

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1720398219  55 DDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22624     7 VTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETC 52

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 60.73 E-value: 2.25e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22596     2 SCKLPPDAGPCFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 60.70 E-value: 2.69e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22631     1 CLLGQDAGSCQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438675 Cd Length: 55 Bit Score: 60.52 E-value: 3.23e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:cd22632     4 CQLPPARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTCK 55

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 60.46 E-value: 3.49e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22629     3 CKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 60.09 E-value: 3.49e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22638     1 CTLKPETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Kunitz-type serine protease inhibitor 6 (BmTI-6), A (BmTI-A), and similar proteins; This group includes Kunitz-type serine protease inhibitors 6 (BmTI-6) and A (BmTI-A), both of which inhibit bovine trypsin, bovine chymotrypsin, human plasmin, human plasma kallikrein and human neutrophil elastase, but not bovine thrombin, human factor Xa or porcine pancreatic kallikrein. They may play a role in blocking blood coagulation during the larvae fixation on cattle. This subfamily also includes Rhipicephalus microplus protease inhibitor carrapatin. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438647 [Multi-domain] Cd Length: 56 Bit Score: 60.16 E-value: 3.84e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22604     6 CSPTADSGPCFAYFPMWWYNVKTGQCEEFIYGGCQGNDNRYETEEECEKTC 56

Kunitz-type domain 2 (K2) of Ixolaris, and similar proteins; This model includes the second Kunitz-type domain (K2) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. This model contains K2, an extraordinarily dynamic domain that encompasses several residues involved in FX binding. Its backbone plasticity is critical for ixolaris biological activity. This domain contains 2 disulfide bonds instead of the 3 typical of Kunitz domain proteins.

Pssm-ID: 438669 Cd Length: 51 Bit Score: 60.17 E-value: 4.26e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22626     1 CSLELDYGVGKAYIPRWYFNTSNARCEMFIFGGIGGNKNNFETLEECKKTC 51

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438667 Cd Length: 61 Bit Score: 59.84 E-value: 6.15e-12

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1720398219 126 DPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKICE 172
Cdd:cd22624     7 VTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETCS 53

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

Pssm-ID: 438663 Cd Length: 58 Bit Score: 59.89 E-value: 6.30e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCKTG 278
Cdd:cd22620     3 CQLPSDTGRGKASFTRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKECAQG 56

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 59.29 E-value: 8.31e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22613     4 CAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

Pssm-ID: 438663 Cd Length: 58 Bit Score: 59.12 E-value: 9.60e-12

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22620     3 CQLPSDTGRGKASFTRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKEC 53

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438661 Cd Length: 53 Bit Score: 59.09 E-value: 1.11e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:cd22618     2 CSEPKVVGPCKAYFPRFYFDSETGKCTPFIYGGCGGNGNNFETLHACRAICR 53

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438638 Cd Length: 56 Bit Score: 58.99 E-value: 1.17e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219 118 PDFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22595     1 PKFCKLPVRPGPCKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 54

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 58.81 E-value: 1.28e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  50 CAMKADDG-PCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22635     1 CLLDKDAGtVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 58.42 E-value: 1.44e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 120 FCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22592     1 FCLEPPYTGPCKARIIRYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 52

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438664 Cd Length: 53 Bit Score: 58.25 E-value: 1.98e-11

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1720398219  57 GPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22621    10 GRCRASFPRWWYNATSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 57.97 E-value: 2.36e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22639     1 CSLPKDRGPCRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVC 51

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 57.75 E-value: 2.59e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22637     1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438666 Cd Length: 59 Bit Score: 57.94 E-value: 2.82e-11

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1720398219  57 GPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22623    13 GPCRGSFPRWHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSAC 56

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438664 Cd Length: 53 Bit Score: 57.87 E-value: 2.87e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22621     1 DFCHLPKVVGRCRASFPRWWYNATSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438650 Cd Length: 52 Bit Score: 57.44 E-value: 3.30e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219  49 FCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22607     1 VCSEQAETGPCRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438664 Cd Length: 53 Bit Score: 57.48 E-value: 3.54e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22621     3 CHLPKVVGRCRASFPRWWYNATSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438670 Cd Length: 53 Bit Score: 57.26 E-value: 3.71e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22627     3 CLLPMDEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 57.37 E-value: 4.05e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22637     1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438638 Cd Length: 56 Bit Score: 57.06 E-value: 5.79e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219 222 RPWCLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22595     1 PKFCKLPVRPGPCKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 54

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438650 Cd Length: 52 Bit Score: 56.66 E-value: 6.19e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 120 FCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22607     1 VCSEQAETGPCRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

Kunitz domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438660 Cd Length: 54 Bit Score: 56.62 E-value: 7.67e-11

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22617     4 CREVPDEGPCRALITRYFYNMTSMRCEEFTYGGCYGNGNNFRDKSSCISAC 54

Kunitz-type domain 2 (K2) of Ixolaris, and similar proteins; This model includes the second Kunitz-type domain (K2) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. This model contains K2, an extraordinarily dynamic domain that encompasses several residues involved in FX binding. Its backbone plasticity is critical for ixolaris biological activity. This domain contains 2 disulfide bonds instead of the 3 typical of Kunitz domain proteins.

Pssm-ID: 438669 Cd Length: 51 Bit Score: 55.93 E-value: 1.39e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22626     1 CSLELDYGVGKAYIPRWYFNTSNARCEMFIFGGIGGNKNNFETLEECKKTC 51

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 55.82 E-value: 1.44e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22637     1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

Pssm-ID: 438663 Cd Length: 58 Bit Score: 56.04 E-value: 1.58e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTCIPG 103
Cdd:cd22620     3 CQLPSDTGRGKASFTRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKECAQG 56

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438661 Cd Length: 53 Bit Score: 55.62 E-value: 1.63e-10

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1720398219 128 GLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22618     9 GPCKAYFPRFYFDSETGKCTPFIYGGCGGNGNNFETLHACRAIC 52

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 55.39 E-value: 2.01e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720398219 221 GRPWCLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22614     1 KPDFCFLEEDPGICRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTC 55

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438665 Cd Length: 53 Bit Score: 55.44 E-value: 2.15e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22622     3 CAAPRVTGPCRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438661 Cd Length: 53 Bit Score: 54.85 E-value: 2.94e-10

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1720398219  57 GPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22618     9 GPCKAYFPRFYFDSETGKCTPFIYGGCGGNGNNFETLHACRAIC 52

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438654 Cd Length: 57 Bit Score: 55.10 E-value: 3.08e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSCK 276
Cdd:cd22611     3 CSLPKESGPCMAYFPRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNICK 54

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438650 Cd Length: 52 Bit Score: 54.74 E-value: 3.78e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22607     2 CSEQAETGPCRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 54.68 E-value: 4.06e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22629     3 CKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

second Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the second Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438645 Cd Length: 51 Bit Score: 54.47 E-value: 4.17e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22602     1 CSLPSKVGPCRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438654 Cd Length: 57 Bit Score: 54.33 E-value: 6.24e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22611     3 CSLPKESGPCMAYFPRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNIC 53

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 53.77 E-value: 7.03e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22631     1 CLLGQDAGSCQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

second Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the second Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438645 Cd Length: 51 Bit Score: 53.31 E-value: 9.40e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22602     1 CSLPSKVGPCRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 53.44 E-value: 9.50e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22628     1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438640 Cd Length: 55 Bit Score: 53.54 E-value: 9.61e-10

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22597     4 CRLPIVPGPCKGFVDLWAFDAVQGKCVPFSYGGCQGNGNKFYSEKECEEYC 54

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 52.22 E-value: 2.25e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22593     1 CSLPLDEGSGNSSLTRWYYDPKKGQCKPFTYKGKGGNENNFLTKEDCEETC 51

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 51.98 E-value: 3.11e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22605     2 CLKEPDREDCGEEQVRWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

Kunitz-type toxin huwentoxin-XI; This model contains Kunitz-type serine protease inhibitor huwentoxin-XI, including U15-theraphotoxin-Hs1g (also called U15-TRTX-Hs1g or Huwentoxin HW11c39), and kappaPI-theraphotoxin-Hs1a (also called KappaPI-TRTX-Hs1a or Huwentoxin-HW11g8). Huwentoxin-XI is a bifunctional toxin that inhibits both serine proteases (trypsin) and voltage-gated potassium channels (Kv) via surfaces displayed on opposite faces of the toxin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438641 Cd Length: 53 Bit Score: 51.92 E-value: 3.39e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATgkCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22598     3 CRLPSDRGRCKASFERWYFNGRT--CAKFIYGGCGGNDNKFPTQEACMKRC 51

first Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the first Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438644 Cd Length: 55 Bit Score: 51.74 E-value: 4.11e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22601     4 CDLPADRGPCTAYIPRWFYNKTTKKCEKFVYGGCQGNKNRFETKDDCLANC 54

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 51.46 E-value: 4.85e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22631     1 CLLGQDAGSCQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438640 Cd Length: 55 Bit Score: 51.23 E-value: 6.18e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKICE 172
Cdd:cd22597     4 CRLPIVPGPCKGFVDLWAFDAVQGKCVPFSYGGCQGNGNKFYSEKECEEYCG 55

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438665 Cd Length: 53 Bit Score: 51.20 E-value: 6.25e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22622     1 EYCAAPRVTGPCRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

Kunitz-type toxin huwentoxin-XI; This model contains Kunitz-type serine protease inhibitor huwentoxin-XI, including U15-theraphotoxin-Hs1g (also called U15-TRTX-Hs1g or Huwentoxin HW11c39), and kappaPI-theraphotoxin-Hs1a (also called KappaPI-TRTX-Hs1a or Huwentoxin-HW11g8). Huwentoxin-XI is a bifunctional toxin that inhibits both serine proteases (trypsin) and voltage-gated potassium channels (Kv) via surfaces displayed on opposite faces of the toxin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438641 Cd Length: 53 Bit Score: 50.76 E-value: 9.47e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYThqCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22598     3 CRLPSDRGRCKASFERWYFNGRT--CAKFIYGGCGGNDNKFPTQEACMKRC 51

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438670 Cd Length: 53 Bit Score: 50.71 E-value: 1.05e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22627     1 DPCLLPMDEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438670 Cd Length: 53 Bit Score: 50.32 E-value: 1.12e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22627     3 CLLPMDEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 50.36 E-value: 1.22e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22628     1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438640 Cd Length: 55 Bit Score: 49.69 E-value: 2.19e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22597     4 CRLPIVPGPCKGFVDLWAFDAVQGKCVPFSYGGCQGNGNKFYSEKECEEYC 54

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438677 Cd Length: 57 Bit Score: 49.82 E-value: 2.46e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720398219 225 CLQPA-----DSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22634     2 CGQPHslgggDGISCFAYIPSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

Kunitz-type serine protease inhibitor subunit of beta 2-bungarotoxin, and similar proteins; This model includes the Kunitz inhibitor subunit of beta 2-bungarotoxin, a presynaptic neurotoxin of the Bungarus multicinctus venom. Beta-bungarotoxin is a heterodimeric neurotoxin consisting of a phospholipase subunit linked by a disulfide bond to the Kunitz protease inhibitor subunit; the latter subunit is homologous to venom basic protease inhibitors but has no protease inhibitor activity and is non-toxic. The beta-bungarotoxin Kunitz subunit serves to guide the toxin to its site of action on the presynaptic membrane by virtue of a high-affinity interaction with a specific subclass of voltage-sensitive potassium channels. This subfamily also includes Kunitz-type serine protease inhibitor homolog beta-bungarotoxin B1 chain and protease inhibitor-like protein 1 (PILP-1). The B1 chain also has no protease inhibitor activity but blocks voltage-gated potassium channels, while PILP-1 inhibits trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438662 Cd Length: 58 Bit Score: 49.09 E-value: 3.96e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219 222 RPWCLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22619     4 HPDCDKPPDTKRCKRVVRAFYYNPSAKTCLQFVYGGCNGNGNHFKSKALCRCHC 57

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 47.60 E-value: 1.08e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 225 CLQPADSGLCKASERRFYYNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22630     3 CSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 53

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 47.22 E-value: 1.75e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22593     1 CSLPLDEGSGNSSLTRWYYDPKKGQCKPFTYKGKGGNENNFLTKEDCEETC 51

Kunitz-type toxin huwentoxin-XI; This model contains Kunitz-type serine protease inhibitor huwentoxin-XI, including U15-theraphotoxin-Hs1g (also called U15-TRTX-Hs1g or Huwentoxin HW11c39), and kappaPI-theraphotoxin-Hs1a (also called KappaPI-TRTX-Hs1a or Huwentoxin-HW11g8). Huwentoxin-XI is a bifunctional toxin that inhibits both serine proteases (trypsin) and voltage-gated potassium channels (Kv) via surfaces displayed on opposite faces of the toxin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438641 Cd Length: 53 Bit Score: 46.52 E-value: 3.30e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 119 DFCFLEEDPGLCRGYMKRYLYNNQTkqCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22598     1 DTCRLPSDRGRCKASFERWYFNGRT--CAKFIYGGCGGNDNKFPTQEACMKRC 51

Kunitz-type domain 1 (K1) of Ixolaris, and similar proteins; This model includes the first Kunitz-type domain (K1) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. While K2 is an extraordinarily dynamic domain that encompasses several residues involved in FX binding, K1 domain keeps as a rigid platform supporting the conformational dynamic of the K2 domain, forming a salt bridge with FXa. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438668 Cd Length: 53 Bit Score: 46.10 E-value: 3.81e-07

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 1720398219 134 MKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22625    16 TKRYGYNKKTQQCEEFLGTECGGGGNSFEEAKECWSSC 53

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 45.81 E-value: 4.58e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219 121 CFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22605     2 CLKEPDREDCGEEQVRWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 45.81 E-value: 4.91e-07

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1720398219  50 CAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22605     2 CLKEPDREDCGEEQVRWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

Kunitz-type domain 1 (K1) of Ixolaris, and similar proteins; This model includes the first Kunitz-type domain (K1) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. While K2 is an extraordinarily dynamic domain that encompasses several residues involved in FX binding, K1 domain keeps as a rigid platform supporting the conformational dynamic of the K2 domain, forming a salt bridge with FXa. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438668 Cd Length: 53 Bit Score: 44.94 E-value: 1.18e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1720398219 225 CLQPADSGL-CKASERRFY-YNSATGKCHRFNYTGCGGNNNNFTTRRRCLRSC 275
Cdd:cd22625     1 CTLPIQEITtCESQPTKRYgYNKKTQQCEEFLGTECGGGGNSFEEAKECWSSC 53

Micrurus tener tener Kunitz-type neurotoxin MitTx-alpha; Micrurus tener tener Kunitz-type neurotoxin MitTx-alpha is a subunit of the pain-inducing, heterodimeric polypeptide toxin that activates acid sensing ion channel a (ASIC1a) at nanomolar concentrations in a pH-independent manner. Acid sensing ion channels (ASICs) are sodium-selective, voltage-independent and amiloride-blockable ion channels that detect extracellular protons produced during inflammation or ischemic injury, and belong to the superfamily of degenerin/epithelial sodium channels. Subtype ASICa is expressed by primary afferent sensory neurons and is activated by MitTx. MitTx consists of two, non-covalently associated alpha and beta subunits that resemble Kunitz and phospholipase-A2 proteins, respectively, and together they function as a potent and selective ASIC1a agonist. The MitTx-alpha structures is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438653 Cd Length: 59 Bit Score: 43.47 E-value: 4.90e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1720398219 117 RPDFCFleEDPGL---CRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22610     2 RPAFCY--EDPPFfqkCGAFVDSYYFNRSRITCVHFFYGQCDVNQNHFTTMSECNRVC 57

Kunitz-type domain 1 (K1) of Ixolaris, and similar proteins; This model includes the first Kunitz-type domain (K1) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. While K2 is an extraordinarily dynamic domain that encompasses several residues involved in FX binding, K1 domain keeps as a rigid platform supporting the conformational dynamic of the K2 domain, forming a salt bridge with FXa. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438668 Cd Length: 53 Bit Score: 43.02 E-value: 4.92e-06

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1720398219  66 YFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22625    19 YGYNKKTQQCEEFLGTECGGGGNSFEEAKECWSSC 53

Micrurus tener tener Kunitz-type neurotoxin MitTx-alpha; Micrurus tener tener Kunitz-type neurotoxin MitTx-alpha is a subunit of the pain-inducing, heterodimeric polypeptide toxin that activates acid sensing ion channel a (ASIC1a) at nanomolar concentrations in a pH-independent manner. Acid sensing ion channels (ASICs) are sodium-selective, voltage-independent and amiloride-blockable ion channels that detect extracellular protons produced during inflammation or ischemic injury, and belong to the superfamily of degenerin/epithelial sodium channels. Subtype ASICa is expressed by primary afferent sensory neurons and is activated by MitTx. MitTx consists of two, non-covalently associated alpha and beta subunits that resemble Kunitz and phospholipase-A2 proteins, respectively, and together they function as a potent and selective ASIC1a agonist. The MitTx-alpha structures is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438653 Cd Length: 59 Bit Score: 42.70 E-value: 8.09e-06

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 1720398219  59 CKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22610    16 CGAFVDSYYFNRSRITCVHFFYGQCDVNQNHFTTMSECNRVC 57

Kunitz-type serine protease inhibitor subunit of beta 2-bungarotoxin, and similar proteins; This model includes the Kunitz inhibitor subunit of beta 2-bungarotoxin, a presynaptic neurotoxin of the Bungarus multicinctus venom. Beta-bungarotoxin is a heterodimeric neurotoxin consisting of a phospholipase subunit linked by a disulfide bond to the Kunitz protease inhibitor subunit; the latter subunit is homologous to venom basic protease inhibitors but has no protease inhibitor activity and is non-toxic. The beta-bungarotoxin Kunitz subunit serves to guide the toxin to its site of action on the presynaptic membrane by virtue of a high-affinity interaction with a specific subclass of voltage-sensitive potassium channels. This subfamily also includes Kunitz-type serine protease inhibitor homolog beta-bungarotoxin B1 chain and protease inhibitor-like protein 1 (PILP-1). The B1 chain also has no protease inhibitor activity but blocks voltage-gated potassium channels, while PILP-1 inhibits trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438662 Cd Length: 58 Bit Score: 42.16 E-value: 1.28e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720398219 117 RPDfCFLEEDPGLCRGYMKRYLYNNQTKQCERFVYGGCLGNRNNFETLDECKKIC 171
Cdd:cd22619     4 HPD-CDKPPDTKRCKRVVRAFYYNPSAKTCLQFVYGGCNGNGNHFKSKALCRCHC 57

Kunitz-type serine protease inhibitor subunit of beta 2-bungarotoxin, and similar proteins; This model includes the Kunitz inhibitor subunit of beta 2-bungarotoxin, a presynaptic neurotoxin of the Bungarus multicinctus venom. Beta-bungarotoxin is a heterodimeric neurotoxin consisting of a phospholipase subunit linked by a disulfide bond to the Kunitz protease inhibitor subunit; the latter subunit is homologous to venom basic protease inhibitors but has no protease inhibitor activity and is non-toxic. The beta-bungarotoxin Kunitz subunit serves to guide the toxin to its site of action on the presynaptic membrane by virtue of a high-affinity interaction with a specific subclass of voltage-sensitive potassium channels. This subfamily also includes Kunitz-type serine protease inhibitor homolog beta-bungarotoxin B1 chain and protease inhibitor-like protein 1 (PILP-1). The B1 chain also has no protease inhibitor activity but blocks voltage-gated potassium channels, while PILP-1 inhibits trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438662 Cd Length: 58 Bit Score: 41.39 E-value: 2.24e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1720398219  47 HTFCAMKADDGPCKAMIRSYFFNMYTHQCEEFIYGGCEGNENRFDTLEECKKTC 100
Cdd:cd22619     4 HPDCDKPPDTKRCKRVVRAFYYNPSAKTCLQFVYGGCNGNGNHFKSKALCRCHC 57