PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II (GCPII)-like. This group contains various PA domain-containing proteins similar to GCPII including, GCPIII (NAALADase2) and NAALADase L. These proteins belong to the peptidase M28 family. GCPII is also known N-acetylated-alpha-linked acidic dipeptidase (NAALDase1), folate hydrolase or prostate-specific membrane antigen (PSMA). GCPII is found in various human tissues including prostate, small intestine, and the central nervous system. In the brain, GCPII is known as NAALDase1, it functions as a NAALDase hydrolyzing the neuropeptide N-acetyl-L-aspartyl-L-glutamate (alpha-NAAG), to release free glutamate. In the small intestine, GCPII releases the terminal glutamate from poly-gamma-glutamated folates. GCPII (PSMA) is a useful cancer marker; its expression is markedly increased in prostate cancer and in tumor-associated neovasculature. GCPIII hydrolyzes alpha-NAAG with a lower efficiency than does GCPII; NAALADase L is not able to hydrolyze alpha-NAAG. The GCPII PA domain (referred to as the apical domain) participates in substrate binding and may act as a protein-protein interaction domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 109 PSQEQPNVVDIVGPTGgiihschRTEENVTG-EQGGPDVVQPYAAYAPSGTPQGLLVYANRGAEEDFKELQTQGIKLEGT 187
Cdd:cd02121    1 PVKRSLILTKPDGATG-------KLIEDTVLeEPPSPDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVKGK 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 188 IALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPADINDGLSSPDETFPNSWYLPPSGVERGSYY---EYFGDPLTPYLPAV 264
Cdd:cd02121   74 IVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENGKTYPDGPARPPSGVQRGSVLfmsIGPGDPLTPGYPSK 153

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967367 265 PSSFRVDLANVSGFPPIPTQPIGFQDARDLLCNLNGTLAPATWQGALGCHYRLGPGfrpdGDFPADSQVNV 335
Cdd:cd02121  154 PGAERRDKEESKGLPKIPSLPISYRDAQPLLKALGGPGAPSDWQGGLPVTYRLGFG----GPSPGKVRVNL 220

Zinc peptidases M18, M20, M28, and M42; Zinc peptidases play vital roles in metabolic and signaling pathways throughout all kingdoms of life. This hierarchy contains zinc peptidases that correspond to the MH clan in the MEROPS database, which contains 4 families (M18, M20, M28, M42). The peptidase M20 family includes carboxypeptidases such as the glutamate carboxypeptidase from Pseudomonas, the thermostable carboxypeptidase Ss1 of broad specificity from archaea and yeast Gly-X carboxypeptidase. The dipeptidases include bacterial dipeptidase, peptidase V (PepV), a non-specific eukaryotic dipeptidase, and two Xaa-His dipeptidases (carnosinases). There is also the bacterial aminopeptidase, peptidase T (PepT) that acts only on tripeptide substrates and has therefore been termed a tripeptidase. Peptidase family M28 contains aminopeptidases and carboxypeptidases, and has co-catalytic zinc ions. However, several enzymes in this family utilize other first row transition metal ions such as cobalt and manganese. Each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. The aminopeptidases in this family are also called bacterial leucyl aminopeptidases, but are able to release a variety of N-terminal amino acids. IAP aminopeptidase and aminopeptidase Y preferentially release basic amino acids while glutamate carboxypeptidase II preferentially releases C-terminal glutamates. Glutamate carboxypeptidase II and plasma glutamate carboxypeptidase hydrolyze dipeptides. Peptidase families M18 and M42 contain metallo-aminopeptidases. M18 is widely distributed in bacteria and eukaryotes. However, only yeast aminopeptidase I and mammalian aspartyl aminopeptidase have been characterized in detail. Some M42 (also known as glutamyl aminopeptidase) enzymes exhibit aminopeptidase specificity while others also have acylaminoacyl-peptidase activity (i.e. hydrolysis of acylated N-terminal residues).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367  46 ETVMGQLDAHRIRENLRELSREPHLASSPRDEDLVQLLLQRWKDPesGLDSAEASTYEVLL-----SFPSQEQPNVVDIV 120
Cdd:cd08022    2 KILLDEPDAENIREWLRYYTSGPHLAGTEGNLELAQWTEDKWREF--GLDDVELEEYDVPIwnvigTIRGSEEPDEYIIL 79

                 .
gi 767967367 121 G 121
Cdd:cd08022   80 G 80

PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II (GCPII)-like. This group contains various PA domain-containing proteins similar to GCPII including, GCPIII (NAALADase2) and NAALADase L. These proteins belong to the peptidase M28 family. GCPII is also known N-acetylated-alpha-linked acidic dipeptidase (NAALDase1), folate hydrolase or prostate-specific membrane antigen (PSMA). GCPII is found in various human tissues including prostate, small intestine, and the central nervous system. In the brain, GCPII is known as NAALDase1, it functions as a NAALDase hydrolyzing the neuropeptide N-acetyl-L-aspartyl-L-glutamate (alpha-NAAG), to release free glutamate. In the small intestine, GCPII releases the terminal glutamate from poly-gamma-glutamated folates. GCPII (PSMA) is a useful cancer marker; its expression is markedly increased in prostate cancer and in tumor-associated neovasculature. GCPIII hydrolyzes alpha-NAAG with a lower efficiency than does GCPII; NAALADase L is not able to hydrolyze alpha-NAAG. The GCPII PA domain (referred to as the apical domain) participates in substrate binding and may act as a protein-protein interaction domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 109 PSQEQPNVVDIVGPTGgiihschRTEENVTG-EQGGPDVVQPYAAYAPSGTPQGLLVYANRGAEEDFKELQTQGIKLEGT 187
Cdd:cd02121    1 PVKRSLILTKPDGATG-------KLIEDTVLeEPPSPDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVKGK 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 188 IALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPADINDGLSSPDETFPNSWYLPPSGVERGSYY---EYFGDPLTPYLPAV 264
Cdd:cd02121   74 IVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENGKTYPDGPARPPSGVQRGSVLfmsIGPGDPLTPGYPSK 153

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967367 265 PSSFRVDLANVSGFPPIPTQPIGFQDARDLLCNLNGTLAPATWQGALGCHYRLGPGfrpdGDFPADSQVNV 335
Cdd:cd02121  154 PGAERRDKEESKGLPKIPSLPISYRDAQPLLKALGGPGAPSDWQGGLPVTYRLGFG----GPSPGKVRVNL 220

Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein turnover, chaperones, Amino acid transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 343 LRNSSNVLGIIRGAVEPDRYVLYGNHRDSWVH---GAVDPSSGTAVLLELSRVLgtllKKGTWRPRRSIVFASWGAEEFG 419
Cdd:COG2234   43 GGDSRNVIAEIPGTDPPDEVVVLGAHYDSVGSigpGADDNASGVAALLELARAL----AALGPKPKRTIRFVAFGAEEQG 118

                         90       100
                 ....*....|....*....|....*.
gi 767967367 420 LIGSTEFTEEFFNKLqERTVAYINVD 445
Cdd:COG2234  119 LLGSRYYAENLKAPL-EKIVAVLNLD 143

M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific membrane antigen (PSMA, also called glutamate carboxypeptidase II or GCP-II)-like subfamily. PSMA is a homodimeric type II transmembrane protein containing three distinct domains: protease-like, apical or protease-associated (PA) and helical domains. The protease-like domain is a large extracellular portion (ectodomain). PSMA is over-expressed predominantly in prostate cancer (PCa) as well as in the neovasculature of most solid tumors, but not in the vasculature of the normal tissues. PSMA is considered a biomarker for PCa and possibly for use as an imaging and therapeutic target. The extracellular domain of PSMA possesses two unique enzymatic functions: N-acetylated, alpha-linked acidic dipeptidase (NAALADase) which cleaves terminal glutamate from the neurodipeptide N-acetyl-aspartyl-glutamate (NAAG), and folate hydrolase (FOLH) which cleaves the terminal glutamates from gamma-linked polyglutamates (carboxypeptidase). A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. Inhibition of GCP-II has been shown to be effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367  46 ETVMGQLDAHRIRENLRELSREPHLASSPRDEDLVQLLLQRWKDPesGLDSAEASTYEVLL-----SFPSQEQPNVVDIV 120
Cdd:cd08022    2 KILLDEPDAENIREWLRYYTSGPHLAGTEGNLELAQWTEDKWREF--GLDDVELEEYDVPIwnvigTIRGSEEPDEYIIL 79

                 .
gi 767967367 121 G 121
Cdd:cd08022   80 G 80

PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II (GCPII)-like. This group contains various PA domain-containing proteins similar to GCPII including, GCPIII (NAALADase2) and NAALADase L. These proteins belong to the peptidase M28 family. GCPII is also known N-acetylated-alpha-linked acidic dipeptidase (NAALDase1), folate hydrolase or prostate-specific membrane antigen (PSMA). GCPII is found in various human tissues including prostate, small intestine, and the central nervous system. In the brain, GCPII is known as NAALDase1, it functions as a NAALDase hydrolyzing the neuropeptide N-acetyl-L-aspartyl-L-glutamate (alpha-NAAG), to release free glutamate. In the small intestine, GCPII releases the terminal glutamate from poly-gamma-glutamated folates. GCPII (PSMA) is a useful cancer marker; its expression is markedly increased in prostate cancer and in tumor-associated neovasculature. GCPIII hydrolyzes alpha-NAAG with a lower efficiency than does GCPII; NAALADase L is not able to hydrolyze alpha-NAAG. The GCPII PA domain (referred to as the apical domain) participates in substrate binding and may act as a protein-protein interaction domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 109 PSQEQPNVVDIVGPTGgiihschRTEENVTG-EQGGPDVVQPYAAYAPSGTPQGLLVYANRGAEEDFKELQTQGIKLEGT 187
Cdd:cd02121    1 PVKRSLILTKPDGATG-------KLIEDTVLeEPPSPDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVKGK 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 188 IALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPADINDGLSSPDETFPNSWYLPPSGVERGSYY---EYFGDPLTPYLPAV 264
Cdd:cd02121   74 IVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENGKTYPDGPARPPSGVQRGSVLfmsIGPGDPLTPGYPSK 153

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967367 265 PSSFRVDLANVSGFPPIPTQPIGFQDARDLLCNLNGTLAPATWQGALGCHYRLGPGfrpdGDFPADSQVNV 335
Cdd:cd02121  154 PGAERRDKEESKGLPKIPSLPISYRDAQPLLKALGGPGAPSDWQGGLPVTYRLGFG----GPSPGKVRVNL 220

M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor (TfR) and prostate-specific membrane antigen (PSMA, also called glutamate carboxypeptidase or GCP-II) subfamily. TfR and PSMA are homodimeric type II transmembrane proteins containing three distinct domains: protease-like, apical or protease-associated (PA) and helical domains. The protease-like domain is a large extracellular portion (ectodomain). In TfR, it contains a binding site for the transferrin molecule and has 28% identity to membrane glutamate carboxypeptidase II (mGCP-II or PSMA). The PA domain is inserted between the first and second strands of the central beta sheet in the protease-like domain. TfR1 is widely expressed, and is a key player in the uptake of iron-loaded transferrin (Tf) into cells. The TfR1 homodimer binds two molecules of Tf and the complex is then internalized. TfR1 may also participate in cell growth and proliferation. TfR2 binds Tf but with a significantly lower affinity than TfR1. It is expressed chiefly in hepatocytes, hematopoietic cells, and duodenal crypt cells; its expression overlaps with that of hereditary hemochromatosis protein (HFE). TfR2 is involved in iron homeostasis; in humans, mutations in TfR2 are associated with a form of hemochromatosis (HFE3). PSMA is over-expressed predominantly in prostate cancer (PCa) as well as in the neovasculature of most solid tumors, but not in the vasculature of normal tissues. PSMA is considered a biomarker for PCa and possibly for use as an imaging and therapeutic target. The extracellular domain of PSMA possesses two unique enzymatic functions: N-acetylated, alpha-linked acidic dipeptidase (NAALADase) which cleaves terminal glutamate from the neurodipeptide N-acetyl-aspartyl-glutamate (NAAG), and folate hydrolase (FOLH) which cleaves the terminal glutamates from gamma-linked polyglutamates (carboxypeptidase). A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants. While related in sequence to peptidase M28 GCP-II, TfR lacks the metal ion coordination centers and protease activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 348 NVLGIIRGAVEPDRYVLYGNHRDSWVHGAVDPSSGTAVLLELSRVLGTLLKKGTWRPRRSIVFASWGAEEFGLIGSTEFT 427
Cdd:cd03874   59 NVVGKIEGIEQPDRAIIIGAHRDSWGYGAGYPNSGTAVLLEIARLFQQLKKKFGWKPLRTIYFISWDGSEFGLAGSTELG 138

                         90       100       110
                 ....*....|....*....|....*....|...
gi 767967367 428 EEFFNKLQERTVAYINVDISV-----FDPLTRP 455
Cdd:cd03874  139 EDRKASLKDEVYAYINIDQLVignseLDVDAHP 171

Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein turnover, chaperones, Amino acid transport and metabolism];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 343 LRNSSNVLGIIRGAVEPDRYVLYGNHRDSWVH---GAVDPSSGTAVLLELSRVLgtllKKGTWRPRRSIVFASWGAEEFG 419
Cdd:COG2234   43 GGDSRNVIAEIPGTDPPDEVVVLGAHYDSVGSigpGADDNASGVAALLELARAL----AALGPKPKRTIRFVAFGAEEQG 118

                         90       100
                 ....*....|....*....|....*.
gi 767967367 420 LIGSTEFTEEFFNKLqERTVAYINVD 445
Cdd:COG2234  119 LLGSRYYAENLKAPL-EKIVAVLNLD 143

M28 Zn-peptidases include aminopeptidases and carboxypeptidases; Peptidase M28 family (also called aminopeptidase Y family) contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. The aminopeptidases in this family are also called bacterial leucyl aminopeptidases, but are able to release a variety of N-terminal amino acids. IAP aminopeptidase and aminopeptidase Y preferentially release basic amino acids while glutamate carboxypeptidase II preferentially releases C-terminal glutamates. Plasma glutamate carboxypeptidase (PGCP) and glutamate carboxypeptidase II (NAALADase) hydrolyze dipeptides. Several members of the M28 peptidase family have PA domain inserts which may participate in substrate binding and/or in promoting conformational changes, which influence the stability and accessibility of the site to substrate. These include prostate-specific membrane antigen (PSMA), yeast aminopeptidase S (SGAP), human transferrin receptors (TfR1 and TfR2), plasma glutamate carboxypeptidase (PGCP) and several predicted aminopeptidases where relatively little is known about them. Also included in the M28 family are glutaminyl cyclases (QC), which are involved in N-terminal glutamine cyclization of many endocrine peptides. Nicastrin and nicalin belong to this family but lack the amino-acid conservation required for catalytically active aminopeptidases.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 346 SSNVLGIIRGAVEPDRYVLYGNHRDSW--VHGAVDPSSGTAVLLELSRVLGTLLKKgtwrPRRSIVFASWGAEEFGLIGS 423
Cdd:cd02690    1 GYNVIATIKGSDKPDEVILIGAHYDSVplSPGANDNASGVAVLLELARVLSKLQLK----PKRSIRFAFWDAEELGLLGS 76

                         90       100
                 ....*....|....*....|...
gi 767967367 424 TEFTEEFFNKLQeRTVAYINVDI 446
Cdd:cd02690   77 KYYAEQLLSSLK-NIRAALNLDM 98

Peptidase family M28;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367  348 NVLGIIRGAvEPDRYVLYGNHRDSWVH--GAVDPSSGTAVLLELSRVLGTLlkkgtWRPRRSIVFASWGAEEFGLIGSTE 425
Cdd:pfam04389   1 NVIAKLPGK-APDEVVLLSAHYDSVGTgpGADDNASGVAALLELARVLAAG-----QRPKRSVRFLFFDAEEAGLLGSHH 74

                          90       100
                  ....*....|....*....|
gi 767967367  426 FTEEffNKLQERTVAYINVD 445
Cdd:pfam04389  75 FAKS--HPPLKKIRAVINLD 92

M28 Zn-peptidase-like; uncharacterized subfamily; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 348 NVLGIIRGAVEPDRYVLYGNHRDSW--VHGAVDPSSGTAVLLELSRvlgtLLKKGTWRPRRSIVFASWGAEEFGLIGSTE 425
Cdd:cd08015    3 NVIAEIPGSDKKDEVVILGAHLDSWhgATGATDNGAGTAVMMEAMR----ILKAIGSKPKRTIRVALWGSEEQGLHGSRA 78

                         90       100
                 ....*....|....*....|....*...
gi 767967367 426 FTEEFF--------NKLQERTVAYINVD 445
Cdd:cd08015   79 YVEKHFgdpptmqlQRDHKKISAYFNLD 106

M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific membrane antigen (PSMA, also called glutamate carboxypeptidase II or GCP-II)-like subfamily. PSMA is a homodimeric type II transmembrane protein containing three distinct domains: protease-like, apical or protease-associated (PA) and helical domains. The protease-like domain is a large extracellular portion (ectodomain). PSMA is over-expressed predominantly in prostate cancer (PCa) as well as in the neovasculature of most solid tumors, but not in the vasculature of the normal tissues. PSMA is considered a biomarker for PCa and possibly for use as an imaging and therapeutic target. The extracellular domain of PSMA possesses two unique enzymatic functions: N-acetylated, alpha-linked acidic dipeptidase (NAALADase) which cleaves terminal glutamate from the neurodipeptide N-acetyl-aspartyl-glutamate (NAAG), and folate hydrolase (FOLH) which cleaves the terminal glutamates from gamma-linked polyglutamates (carboxypeptidase). A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. Inhibition of GCP-II has been shown to be effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367  46 ETVMGQLDAHRIRENLRELSREPHLASSPRDEDLVQLLLQRWKDPesGLDSAEASTYEVLL-----SFPSQEQPNVVDIV 120
Cdd:cd08022    2 KILLDEPDAENIREWLRYYTSGPHLAGTEGNLELAQWTEDKWREF--GLDDVELEEYDVPIwnvigTIRGSEEPDEYIIL 79

                 .
gi 767967367 121 G 121
Cdd:cd08022   80 G 80

M28 Zn-peptidase containing a protease-associated (PA) domain insert and associated with a PDZ domain; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. This subfamily is composed of uncharacterized proteins, many of which contain a protease-associated (PA) domain insert which may participate in substrate binding and/or promote conformational changes, influencing the stability and accessibility of the site to substrate. Proteins in this subfamily are also associated with the PDZ domain, a widespread protein module that has been recruited to serve multiple functions during the course of evolution.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 348 NVLGII-RGAVEPDRYVLYGNHRD---------------SWVH-GAVDPSSGTAVLLELSRVLGTLLKKGTwrPRRSIVF 410
Cdd:cd05663   57 NVIGVLpGKGDVADETVVVGAHYDhlgyggegslargdeSLIHnGADDNASGVAAMLELAAKLVDSDTSLA--LSRNLVF 134

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 767967367 411 ASWGAEEFGLIGSTEFTEEfFNKLQERTVAYINVDI 446
Cdd:cd05663  135 IAFSGEELGLLGSKHFVKN-PPFPIKNTVYMINMDM 169

M28 Zn-Peptidases; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. This subfamily is composed of uncharacterized proteins that do not contain a protease-associated (PA) domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 340 RLELRNSSNVLGIIRGAVEPDRYVLYGNHRD-------SWVHGAVDPSSGTAVLLELSRVLGTllkkgtWRPRRSIVFAS 412
Cdd:cd05662   56 RFSTRQGVNVLAVIKGSEPPTKWRVVSAHYDhlgirggKIYNGADDNASGVAALLALAEYFKK------HPPKHNVIFAA 129

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 767967367 413 WGAEEFGLIGSTEFTEEFFNKLQERTVAyINvdisvFDPLTRPWRPE-------HLRQLDPVL 468
Cdd:cd05662  130 TDAEEPGLRGSYAFVEALKVPRAQIELN-IN-----LDMISRPERNElyvegasQFPQLTSIL 186

PA_hNAALADL2_like: Protease-associated domain containing proteins like human N-acetylated alpha-linked acidic dipeptidase-like 2 protein (hNAALADL2). This group contains various PA domain-containing proteins similar to hNAALADL2. The function of hNAALADL2 is unknown. This gene has been mapped to a chromosomal region associated with Cornelia de Lange syndrome. The significance of the PA domain to hNAALADL2 has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 145 DVVQPYAAYAPSGTPQGLLVYANRGAEEDFKELQTQgIKLEGTIALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPADIND 224
Cdd:cd02131    1 DLLYSYAAYSAKGTLQAEVVDVQYGSVEDLRRIRDN-MNVTNQIALLKLGQAPLLYKLSLLEEAGFGGVLLYVDPCDLPK 79

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967367 225 GLSSPDETFPNSwyLPPSgvergsyyeyfGDPLTPYLPAVPSSFRvdlANVSGFPPIPTQPIGFQDARDLL 295
Cdd:cd02131   80 TRHTWHQAFMVS--LNPG-----------GDPSTPGYPSADQSCR---QCRGNLTSLLVQPISAYLAKKLL 134

PA: Protease-associated (PA) domain. The PA domain is an insert domain in a diverse fraction of proteases. The significance of the PA domain to many of the proteins in which it is inserted is undetermined. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate. Proteins into which the PA domain is inserted include the following: i) various signal peptide peptidases including, hSPPL2a and 2b which catalyze the intramembrane proteolysis of tumor necrosis factor alpha, ii) various proteins containing a C3H2C3 RING finger including, Arabidopsis ReMembR-H2 protein and various E3 ubiquitin ligases such as human GRAIL (gene related to anergy in lymphocytes), iii) EDEM3 (ER-degradation-enhancing mannosidase-like 3 protein), iv) various plant vacuolar sorting receptors such as Pisum sativum BP-80, v) glutamate carboxypeptidase II (GCPII), vi) yeast aminopeptidase Y, vii) Vibrio metschnikovii VapT, a sodium dodecyl sulfate (SDS) resistant extracellular alkaline serine protease, viii) lactocepin (a cell envelope-associated protease from Lactobacillus paracasei subsp. paracasei NCDO 151), ix) various subtilisin-like proteases such as melon Cucumisin, and x) human TfR (transferrin receptor) 1 and 2.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 138 TGEQGGPDVVQPYAAYAPSGTPQGL----LVYANRGAEEDFkelqtqGIKLEGTIALTRYGGVGRGAKAVNAAKHGVAGV 213
Cdd:cd00538    1 DVILATTGYAGSALLFNPPSSPVGVvagpLVGCGYGTTDDS------GADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAV 74

                         90       100       110
                 ....*....|....*....|....*....|.
gi 767967367 214 LVYTDPADINDGLSSPDETFPNSWyLPPSGV 244
Cdd:cd00538   75 IIYNNGDDPGPQMGSVGLESTDPS-IPTVGI 104

M28 Zn-peptidase Aeromonas (Vibrio) proteolytica aminopeptidase; Peptidase family M28; Aeromonas (Vibrio) proteolytica aminopeptidase (AAP; leucine aminopeptidase from Vibrio proteolyticus; Bacterial leucyl aminopeptidase; E.C. 3.4.11.10) subfamily. AAP is a small (32kDa), heat stable leucine aminopeptidase and is active as a monomer. Similar forms of the enzyme have been isolated from Escherichia coli and Staphylococcus thermophilus. Leucine aminopeptidases, in general, play important roles in many biological processes such as protein catabolism, hormone degradation, regulation of migration and cell proliferation, as well as HIV infection and proliferation. AAP is a broad-specificity enzyme, utilizing two zinc(II) ions in its active site to remove N-terminal amino acids, with preference for large hydrophobic amino acids in the P1 position of the substrate, Leu being the most efficiently cleaved. It can accommodate all residues, except Pro, Asp and Glu in the P1' position.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 347 SNVLGIIRGAVEPDRYVLYGNHRDSWVH---------GAVDPSSGTAVLLELSRVLgtlLKKGtWRPRRSIVFASWGAEE 417
Cdd:cd03879   75 PSIIATIPGSEKSDEIVVIGAHQDSINGsnpsngrapGADDDGSGTVTILEALRVL---LESG-FQPKNTIEFHWYAAEE 150

                 ....*.
gi 767967367 418 FGLIGS 423
Cdd:cd03879  151 GGLLGS 156

PA_ScAPY_like: Protease-associated domain containing proteins like Saccharomyces cerevisiae aminopeptidase Y (ScAPY). This group contains various PA domain-containing proteins similar to the S. cerevisiae APY, including Trichophyton rubrum leucine aminopeptidase 1(LAP1). Proteins in this group belong to the peptidase M28 family. ScAPY hydrolyzes amino acid-4-methylcoumaryl-7-amides (MCAs). ScAPY more rapidly hydrolyzes dipeptidyl-MCAs. Hydrolysis of amino acid-MCAs or dipeptides is stimulated by Co2+ while the hydrolysis of dipeptidyl-MCAs, tripeptides, and longer peptides is inhibited by Co2+. ScAPY is vacuolar and is activated by proteolytic processing. LAP1 is a secreted leucine aminopeptidase. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967367 152 AYAPSGTPQGLLVYA-NRG-AEEDFKElqtqgiKLEGTIALTRYGGVGRGAKAVNAAKHGVAGVLVY-TDPADINDG-LS 227
Cdd:cd02130   15 TYSPAGEVTGPLVVVpNLGcDAADYPA------SVAGNIALIERGECPFGDKSALAGAAGAAAAIIYnNVPAGGLSGtLG 88

                 ....*.
gi 767967367 228 SPDETF 233
Cdd:cd02130   89 EPSGPY 94

M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, nicastrin subfamily. Nicastrin is a main component of the gamma-secretase complex, which also contains presenilin, Pen-2 and Aph-1. Its extracellular domain sequence resembles aminopeptidases, but certain catalytic residues are not conserved. It is mainly localized to the endoplasmic reticulum and Golgi. It is highly glycosylated (Mr 120 kDa) and is essential for substrate recognition of the N-terminus of gamma-secretase substrates derived from APP and Notch. Nicastrin facilitates substrate cleavage by the catalytic presenilin subunit in the gamma-secretase complex. One conserved glutamate is especially important, probably because this residue forms an ion pair with the amino terminus of the substrate. This substrate-binding domain is often called the DAP domain (named after DYIGS, the amino acid stretch that modulates amyloid precursor protein (APP) processing, and Peptidase homologous region). The sequence of the substrate N-terminus is apparently not critical for the interaction, but a free amino group is. Thus, nicastrin can be considered a kind of gatekeeper for the gamma-secretase complex: type I membrane proteins that have not shed their ectodomains cannot interact properly with nicastrin and do not gain access to the active site. Dysfunction of gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1).

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 767967367 375 GAVDPSSGTAVLLELSRVLGTLLKKGTWRprRSIVFASWGAEEFGLIGSTEF 426
Cdd:cd03881  231 GADSSLSGFVALLAAAEALKKVDGKGSLK--RNVVFAFFNGESWGYIGSSRF 280

PA_2: Protease-associated (PA) domain subgroup 2. A subgroup of PA-domain containing proteins. The PA domain is an insert domain in a diverse fraction of proteases. The significance of the PA domain to many of the proteins in which it is inserted is undetermined. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate. Proteins in this group contain a C-terminal RING-finger domain. Proteins into which the PA domain is inserted include the following: i) various signal peptide peptidases: such as hSPPL2a and 2b, ii) various E3 ubiquitin ligases similar to human GRAIL (gene related to anergy in lymphocytes) protein, iii) various proteins containing a RING finger motif such as Arabidopsis ReMembR-H2 protein, iv) EDEM3 (ER-degradation-enhancing mannosidase-like 3 protein), v) various plant vacuolar sorting receptors such as Pisum sativum BP-80, vi) prostate-specific membrane antigen (PSMA), vii) yeast aminopeptidase Y viii) Vibrio metschnikovii VapT, a sodium dodecyl sulfate (SDS) resistant extracellular alkaline serine protease, ix) various subtilisin-like proteases such as Cucumisin from the juice of melon fruits, and x) human TfR (transferrin receptor) 1 and human TfR2. The proteins listed above belong to other subgroups; relatively little is known about proteins in this subgroup.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767967367 153 YAPSGTPQGLLVYANRGAEEDFkelqtQGIKLEGTIALTRYGG--VGRGAKAVNAAKHGVAGVLVYtdpaDINDG 225
Cdd:cd04819   17 RSPSGEAKGEPVDAGYGLPKDF-----DGLDLEGKIAVVKRDDpdVDRKEKYAKAVAAGAAAFVVV----NTVPG 82