ADAM-TS Spacer 1; This domain represents the Spacer-1 region from the ADAM-TS and ADAM-TS-like proteins. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase) and is a subfamily of the metalloprotease family, sharing a high degree of sequence similarity and conserved domain organization among its members. Members of the ADAM-TS family have been implicated in a range of diseases. ADAM-TS-like proteins lack a metalloprotease domain. They resides in the ECM and have regulatory roles. Examples of ADAM-TS-like proteins are papilin and punctin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359  185 PVTGTFDSNdLSRGYNQILIIPMGATSIRVEEVAASRNFLAVKNVLGDYYLNGHWTIgGAW--ALPAASTVLRYERgaeG 262
Cdd:pfam05986    1 TVSGSFTEG-RAKGYVTFVTIPAGATHIHIVNRKPSFTHLAVKNVQGKYILNGKGSI-SLNptYPSLLGTVLEYRR---S 75

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 1953408359  263 DLAPERLLARGPTSEPLVVELLSQ---EANPGVRFEYHLP 299
Cdd:pfam05986   76 LPALEELHAPGPTQEDLEIQVLRQygkGTNPGITYEYFIP 115

Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359 1102 QPGVVDAQPGQRIQLTCRAEGFPPPAIEWQRDGQPL-SSPRHELQPDG---SLVISHVAVEDAGFYACVA 1167
Cdd:pfam07679    6 KPKDVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrSSDRFKVTYEGgtyTLTISNVQPDDSGKYTCVA 75

ADAMTS cysteine-rich domain; This cysteine rich domain is found in a variety of ADAMTS and ADAMTS-like endopeptidases widely spread in animals. It is a well-conserved cysteine-rich sequence containing 10 cysteine residues. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase, pfam08516) and consists of at least 20 members sharing a high degree of sequence similarity and conserved domain organization. Members of the ADAMTS family have been implicated in a range of diseases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359   86 DFRAEQCSQLDSQDFQGRR-----YKW---LPYYGAPNRCELNCIPKGENFYYKHREAVVDGTPCEP------GKRDVCV 151
Cdd:pfam19236    4 EFMSQQCARTDGQPLRSSPggasfYHWgaaVPHSQGDALCRHMCRAIGESFIMKRGDSFLDGTRCMPsgpredGTLSLCV 83

                           90       100       110
                   ....*....|....*....|....*....|..
gi 1953408359  152 DGSCRVVGCDHNLDSSKEEDKCLQCGGDGTTC 183
Cdd:pfam19236   84 LGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1953408359  309 WSHGSWSDCSAECGGGHQSRAVFC--TTDDEVYPDHMCQPQLRPADRRPCSTHPC 361
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCvqKGGGSIVPDSECSAQKKPPETQSCNLKPC 55

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1953408359  450 WSAEPWGECSVSCGAGVRRRNVTC-QSDEGALLPATACSSEHRPPTTEPCVHEDC 503
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCvQKGGGSIVPDSECSAQKKPPETQSCNLKPC 55

Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359  962 LEPSLVQAALGQLVQLFCQ---GgtSLDPHARWQKDGQPISSD--RHKLQPDGSLIISPLWAEDAGTYSC 1026
Cdd:cd05724      2 VEPSDTQVAVGEMAVLECSpprG--HPEPTVSWRKDGQPLNLDneRVRIVDDGNLLIAEARKSDEGTYKC 69

ADAM-TS Spacer 1; This domain represents the Spacer-1 region from the ADAM-TS and ADAM-TS-like proteins. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase) and is a subfamily of the metalloprotease family, sharing a high degree of sequence similarity and conserved domain organization among its members. Members of the ADAM-TS family have been implicated in a range of diseases. ADAM-TS-like proteins lack a metalloprotease domain. They resides in the ECM and have regulatory roles. Examples of ADAM-TS-like proteins are papilin and punctin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359  185 PVTGTFDSNdLSRGYNQILIIPMGATSIRVEEVAASRNFLAVKNVLGDYYLNGHWTIgGAW--ALPAASTVLRYERgaeG 262
Cdd:pfam05986    1 TVSGSFTEG-RAKGYVTFVTIPAGATHIHIVNRKPSFTHLAVKNVQGKYILNGKGSI-SLNptYPSLLGTVLEYRR---S 75

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 1953408359  263 DLAPERLLARGPTSEPLVVELLSQ---EANPGVRFEYHLP 299
Cdd:pfam05986   76 LPALEELHAPGPTQEDLEIQVLRQygkGTNPGITYEYFIP 115

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1953408359  796 RCLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSCR 848
Cdd:pfam00014    1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 53

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359 1102 QPGVVDAQPGQRIQLTCRAEGFPPPAIEWQRDGQPL-SSPRHELQPDG---SLVISHVAVEDAGFYACVA 1167
Cdd:pfam07679    6 KPKDVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrSSDRFKVTYEGgtyTLTISNVQPDDSGKYTCVA 75

Immunoglobulin like; IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359  1103 PGVVDAQPGQRIQLTCRAEGFPPPAIEWQRDGQ--PLSSPRHELQPDG---SLVISHVAVEDAGFYACVAFSGQNRAQRW 1177
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSSGSASSG 80

                    ....*
gi 1953408359  1178 VQLRV 1182
Cdd:smart00410   81 TTLTV 85

Fifth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1953408359 1111 GQRIQLTCRAEGFPPPAIEWQRDGQPL-SSPRHELQPDGSLVISHV-AVEDAGFYACVAFSGQNR-AQRWVQLRV 1182
Cdd:cd20958     15 GQTLRLHCPVAGYPISSITWEKDGRRLpLNHRQRVFPNGTLVIENVqRSSDEGEYTCTARNQQGQsASRSVFVKV 89

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1953408359  389 WKMGPWLPCSASCGGGSQSRSVYCISSDGAGVQeaaeEAECAGLPGKPPTTRACNLQRC 447
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGSIV----PDSECSAQKKPPETQSCNLKPC 55

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1953408359    30 WGPWGTWSPCSRTCGGGISFRERPCYSR-RRDGGSNCVGPTRSHRSCHTESCP 81
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPpPQNGGGPCTGEDVETRACNEQPCP 53

Fifth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1953408359 1200 GDTARLLCVVTGESV-NIRWSRNG--LPVradGHRVHQSPDGTLLIHNL-RAGDEGSYTCSAY-RGSQAVSRSTEVKV 1272
Cdd:cd20958     15 GQTLRLHCPVAGYPIsSITWEKDGrrLPL---NHRQRVFPNGTLVIENVqRSSDEGEYTCTARnQQGQSASRSVFVKV 89

Second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of the Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, and Robo3), and three mammalian Slit homologs (Slit-1,Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit-2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359  962 LEPSLVQAALGQLVQLFCQ---GgtSLDPHARWQKDGQPISSD--RHKLQPDGSLIISPLWAEDAGTYSC 1026
Cdd:cd05724      2 VEPSDTQVAVGEMAVLECSpprG--HPEPTVSWRKDGQPLNLDneRVRIVDDGNLLIAEARKSDEGTYKC 69

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359  964 PSLVQAALGQLVQLFCQ-GGTSlDPHARWQKDGQPI-SSDRHKLQPDG---SLIISPLWAEDAGTYSCGSSRP-GHDSQK 1037
Cdd:pfam07679    7 PKDVEVQEGESARFTCTvTGTP-DPEVSWFKDGQPLrSSDRFKVTYEGgtyTLTISNVQPDDSGKYTCVATNSaGEAEAS 85

                   ....*
gi 1953408359 1038 IQLHV 1042
Cdd:pfam07679   86 AELTV 90

Immunoglobulin like; IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359   964 PSLVQAALGQLVQLFCQGGTSLDPHARWQKDGQ--PISSDRHKLQPDG---SLIISPLWAEDAGTYSC-GSSRPGHDSQK 1037
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCaATNSSGSASSG 80

                    ....*
gi 1953408359  1038 IQLHV 1042
Cdd:smart00410   81 TTLTV 85

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1953408359   511 WHVGAWGLCSRSCGSGTRRRQVTCAIRPPGHCRSLQPWKPGEVEPCNTQPCH 562
Cdd:smart00209    2 SEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDVETRACNEQPCP 53

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*...
gi 1953408359   447 CAAWSaePWGECSVSCGAGVRRRNVTCQSDEGaLLPATACSSEHrpPTTEPCVHEDCP 504
Cdd:smart00209    1 WSEWS--EWSPCSVTCGGGVQTRTRSCCSPPP-QNGGGPCTGED--VETRACNEQPCP 53

sporozoite surface protein 2 (SSP2); Provisional

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1953408359   31 GPWGTWSPCSRTCGGGISFRERPCYSrrrdggSNCVgpTRSHRSCHTESCP 81
Cdd:PTZ00441   241 GPWDEWTPCSVTCGKGTHSRSRPILH------EGCT--THMVEECEEEECP 283

ADAM-TS Spacer 1; This domain represents the Spacer-1 region from the ADAM-TS and ADAM-TS-like proteins. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase) and is a subfamily of the metalloprotease family, sharing a high degree of sequence similarity and conserved domain organization among its members. Members of the ADAM-TS family have been implicated in a range of diseases. ADAM-TS-like proteins lack a metalloprotease domain. They resides in the ECM and have regulatory roles. Examples of ADAM-TS-like proteins are papilin and punctin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359  185 PVTGTFDSNdLSRGYNQILIIPMGATSIRVEEVAASRNFLAVKNVLGDYYLNGHWTIgGAW--ALPAASTVLRYERgaeG 262
Cdd:pfam05986    1 TVSGSFTEG-RAKGYVTFVTIPAGATHIHIVNRKPSFTHLAVKNVQGKYILNGKGSI-SLNptYPSLLGTVLEYRR---S 75

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 1953408359  263 DLAPERLLARGPTSEPLVVELLSQ---EANPGVRFEYHLP 299
Cdd:pfam05986   76 LPALEELHAPGPTQEDLEIQVLRQygkGTNPGITYEYFIP 115

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1953408359  796 RCLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSCR 848
Cdd:pfam00014    1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1953408359  797 CLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSC 847
Cdd:cd00109      1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1953408359  797 CLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSC 847
Cdd:cd22629      3 CKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359 1102 QPGVVDAQPGQRIQLTCRAEGFPPPAIEWQRDGQPL-SSPRHELQPDG---SLVISHVAVEDAGFYACVA 1167
Cdd:pfam07679    6 KPKDVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrSSDRFKVTYEGgtyTLTISNVQPDDSGKYTCVA 75

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1953408359  797 CLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSC 847
Cdd:cd22628      1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1953408359  797 CLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSC 847
Cdd:cd22630      3 CSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 53

Immunoglobulin like; IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG.

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                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953408359  1103 PGVVDAQPGQRIQLTCRAEGFPPPAIEWQRDGQ--PLSSPRHELQPDG---SLVISHVAVEDAGFYACVAFSGQNRAQRW 1177
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSSGSASSG 80

                    ....*
gi 1953408359  1178 VQLRV 1182
Cdd:smart00410   81 TTLTV 85

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.

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                   ....*....|....*....|....*....|....*....|....*....|.
gi 1953408359  797 CLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSC 847
Cdd:cd22603      3 CLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Fifth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1953408359 1111 GQRIQLTCRAEGFPPPAIEWQRDGQPL-SSPRHELQPDGSLVISHV-AVEDAGFYACVAFSGQNR-AQRWVQLRV 1182
Cdd:cd20958     15 GQTLRLHCPVAGYPISSITWEKDGRRLpLNHRQRVFPNGTLVIENVqRSSDEGEYTCTARNQQGQsASRSVFVKV 89

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.

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                   ....*....|....*....|....*....|....*....|....*....|.
gi 1953408359  797 CLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSC 847
Cdd:cd22638      1 CTLKPETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 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.

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                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1953408359  794 PVRCLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSCR 848
Cdd:cd22632      1 PSLCQLPPARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTCK 55

Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

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                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1953408359 1114 IQLTCRAEGFPPPAIEWQRDGQPLSS----PRHELQPDGSLVISHVAVEDAGFYACVA 1167
Cdd:cd00096      1 VTLTCSASGNPPPTITWYKNGKPLPPssrdSRRSELGNGTLTISNVTLEDSGTYTCVA 58

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.

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                   ....*....|....*....|....*....|....*....|....*....|.
gi 1953408359  797 CLLPSAHGSCSDWAARWYFVPSVGRCNRFWYGGCHGNGNNFASEEECVSSC 847
Cdd:cd22616      5 CLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

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                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1953408359  309 WSHGSWSDCSAECGGGHQSRAVFC--TTDDEVYPDHMCQPQLRPADRRPCSTHPC 361
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCvqKGGGSIVPDSECSAQKKPPETQSCNLKPC 55