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 1034572725 409 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 488
Cdd:cd08022    59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 489 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 568
Cdd:cd08022   139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 569 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 648
Cdd:cd08022   210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                  ..
gi 1034572725 649 PF 650
Cdd:cd08022   286 PF 287

Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the transferrin receptor as shown in its crystal structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 682 VSFDSLFSAVKNFTEIASKFSER---LQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGE 758
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWakkWEDIKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1034572725 759 SFPGIYDALFDieskvdpsKAWGEVKRQIYVAAFTVQAAAETLS 802
Cdd:pfam04253  81 TFPGIRDAIEA--------GDWELAQKQISIVAKAIQSAAETLK 116

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 1034572725 409 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 488
Cdd:cd08022    59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 489 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 568
Cdd:cd08022   139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 569 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 648
Cdd:cd08022   210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                  ..
gi 1034572725 649 PF 650
Cdd:cd08022   286 PF 287

Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the transferrin receptor as shown in its crystal structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 682 VSFDSLFSAVKNFTEIASKFSER---LQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGE 758
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWakkWEDIKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1034572725 759 SFPGIYDALFDieskvdpsKAWGEVKRQIYVAAFTVQAAAETLS 802
Cdd:pfam04253  81 TFPGIRDAIEA--------GDWELAQKQISIVAKAIQSAAETLK 116

PA domain; The PA (Protease associated) domain is found as an insert domain in diverse proteases. The PA domain is also found in a plant vacuolar sorting receptor Swiss:O22925 and members of the RZF family Swiss:O43567. It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 226 EGDLVYVNYARTEDFFKLERDMKincsGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAP----GVKSYPDGW 301
Cdd:pfam02225   1 TGPLVLAPGCYAGDGIPADFDVK----GKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPpgagGNELYPDGI 76

                          90
                  ....*....|....*
gi 1034572725 302 NLPGGGVQRGNILNL 316
Cdd:pfam02225  77 YIPAVGVSRADGEAL 91

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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1034572725 113 MKAFLDELKaeNIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYD 169
Cdd:cd03874     1 YARKLVDLA--KIKEDLEYLSSMPHMAGTKGDAALAKYIENSFKNNGLFEVELEEYS 55

T9SS-dependent M36 family metallopeptidase; Members of this family have an M36 family metallopeptidase domain, like fungalysin (see PF02128), and a C-terminal T9SS type A sorting domain (see TIGR04131).

                          10        20        30
                  ....*....|....*....|....*....|....
gi 1034572725 252 SGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSD 285
Cdd:NF038113  468 AGKIAVIRRGSCEFAVKVLNAQNAGAIAVIIVNN 501

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 1034572725 409 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 488
Cdd:cd08022    59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 489 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 568
Cdd:cd08022   139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 569 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 648
Cdd:cd08022   210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                  ..
gi 1034572725 649 PF 650
Cdd:cd08022   286 PF 287

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 1034572725 391 NFSTQKVKMHIHStnevtRIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTL-KKEGWRPRR 469
Cdd:cd03874    43 NNGLFEVELEEYS-----PITNVVGKIEGIEQPDRAIIIGAHRDSWGYGAGYPNSGTAVLLEIARLFQQLkKKFGWKPLR 117

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 470 TILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEgfegksly 549
Cdd:cd03874   118 TIYFISWDGSEFGLAGSTELGEDRKASLKDEVYAYINIDQLVIGNSELDVDAHPLLQSLFRKASKKVKFPGN-------- 189

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 550 ESWTKKSPspefsgMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWetnkfSGYPLYHSVYETYELVEKFYDPMFKYHL 629
Cdd:cd03874   190 EDWWKHSP------NAKVSNLHQYGDWTPFLNHLGIPVAVFSFKNDR-----NASYPINSSYDTFEWLEKFLDPDFELHS 258

                         250       260
                  ....*....|....*....|
gi 1034572725 630 TVAQVRGGMVFELANSIVLP 649
Cdd:cd03874   259 TLAEFVGLLVLSLAEDPLLP 278

Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the transferrin receptor as shown in its crystal structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 682 VSFDSLFSAVKNFTEIASKFSER---LQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGE 758
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWakkWEDIKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1034572725 759 SFPGIYDALFDieskvdpsKAWGEVKRQIYVAAFTVQAAAETLS 802
Cdd:pfam04253  81 TFPGIRDAIEA--------GDWELAQKQISIVAKAIQSAAETLK 116

PA_TfR: Protease-associated domain containing proteins like transferrin receptor (TfR). This group contains various PA domain-containing proteins similar to human TfR1 and TfR2. TfR1 and TfR2 are type II membrane proteins, belonging to the peptidase M28 family. TfR1 is homodimeric, widely expressed, and a key player in the uptake of iron-loaded transferrin (Tf) into cells. The TfR1 homodimer binds two molecules of Tf and this complex is internalized. In addition to its role in iron uptake, TfR1 may participate in cell growth and proliferation. TfR2 also binds Tf but with a significantly lower affinity than does TfR1. TfR2 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. HFE and TfR2 interact in cells. By one model for serum iron sensing, at low or basal iron concentrations, HFE and TFR1 form a complex at the plasma membrane; at increased Tf, Tf competes with HFE for binding of TfR1, resulting in HFE disassociating from TfR1 and associating with TfR2 . The TfR1-TfR2 association might initiate a signal cascade leading to the induction of hepcidin (a small peptide hormone that controls systemic iron levels). Human mutations in TfR2 are associated with a form of hemochromatosis (HFE3). The significance of the PA domain to TfRs 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 1034572725 215 PFSAFSPQGMPEGDLVYVNYARTEDFFKLeRDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYfaPGV 294
Cdd:cd02128    19 GYVAYSAAGTVTGKLVYANYGRKKDFEDL-QSVGVSVNGSVVLVRAGKISFAEKVANAEKLGAVGVLIYPDPADF--PID 95

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 295 KSYpdgwNLPGGGVQRgnilnlnGAGDPLTPGYPA-NEYAYRRgiAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPdSS 373
Cdd:cd02128    96 PSE----TALFGHVHL-------GTGDPYTPGFPSfNHTQFPP--SQSSGLPNIPAQTISAAAAAKLLSKMGGPVCP-SG 161

                         170       180
                  ....*....|....*....|....*...
gi 1034572725 374 WRGSLkVPYNVGPGftgnfSTQKVKMHI 401
Cdd:cd02128   162 WKGGD-STCRLGTS-----SSKNVKLTV 183

PA domain; The PA (Protease associated) domain is found as an insert domain in diverse proteases. The PA domain is also found in a plant vacuolar sorting receptor Swiss:O22925 and members of the RZF family Swiss:O43567. It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 226 EGDLVYVNYARTEDFFKLERDMKincsGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAP----GVKSYPDGW 301
Cdd:pfam02225   1 TGPLVLAPGCYAGDGIPADFDVK----GKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPpgagGNELYPDGI 76

                          90
                  ....*....|....*
gi 1034572725 302 NLPGGGVQRGNILNL 316
Cdd:pfam02225  77 YIPAVGVSRADGEAL 91

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 1034572725 210 SDIVPPFSAFSPQGMPEGDLVYVNYARTEDFfklerdmKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADy 289
Cdd:cd00538    11 GSALLFNPPSSPVGVVAGPLVGCGYGTTDDS-------GADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAVIIYNNGDD- 82

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1034572725 290 fapgvksypdgwnlpgGGVQRGNilnlngagdpltpgypaneyayrrgIAEAVGLPSIPVHPIGYYDAQKLLEKMGGS 367
Cdd:cd00538    83 ----------------PGPQMGS-------------------------VGLESTDPSIPTVGISYADGEALLSLLEAG 119

M28 Zn-Peptidase Plasma glutamate carboxypeptidase; Peptidase M28 family; Plasma glutamate carboxypeptidase (PGCP; blood plasma glutamate carboxypeptidase; EC 3.4.17.21) subfamily. PGCP is a 56kDa glutamate carboxypeptidase that is mainly produced in mammalian placenta and kidney, the majority of which is thought to be secreted into the bloodstream. Similar proteins are also found in other species, including bacteria. These proteins contain protease-associated (PA) domain inserts between the first and second strands of the central beta sheet in the protease-like domain. The PA domains may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate. The exact physiological substrates of PGCP are unknown, although this enzyme may play an important role in the hydrolysis of circulating peptides. Its closest homolog encodes an important brain glutamate carboxypeptidase II (NAALADase) identical to the prostate-specific membrane antigen (PSMA), which serves as a marker for prostatic cancer metastasis. Hypermethylation of PGCP gene has been associated with human bronchial epithelial (HBE) cell immortalization and lung cancer. PGCP also provides an attractive target for serological analysis in hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) patients.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 396 KVKMHIHSTNEVTRiYNVIGTLRGAVEPDRYVILGGHRDSWVF--GGIDPQSGAAVVHEIVRSfgtLKKEGWRPRRTILF 473
Cdd:cd03883   213 ELKMEAKTYPDATS-RNVIAEITGSKYPDEVVLVGGHLDSWDVgtGAMDDGGGVAISWEALKL---IKDLGLKPKRTIRV 288

                          90       100
                  ....*....|....*....|.
gi 1034572725 474 ASWDAEEFGLLGSTEWAEENS 494
Cdd:cd03883   289 VLWTGEEQGLVGAKAYAEAHK 309

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 1034572725 211 DIVPPFSAFSPQGMPEGDLVYVNYARTEDFFKLERDMkiNCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADyF 290
Cdd:cd02131     1 DLLYSYAAYSAKGTLQAEVVDVQYGSVEDLRRIRDNM--NVTNQIALLKLGQAPLLYKLSLLEEAGFGGVLLYVDPCD-L 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 291 APGVKSYPDGWnlpgggvqrgnILNLNGAGDPLTPGYPANEYAYRrgiAEAVGLPSIPVHPIGYYDAQKLLekmggSAPP 370
Cdd:cd02131    78 PKTRHTWHQAF-----------MVSLNPGGDPSTPGYPSADQSCR---QCRGNLTSLLVQPISAYLAKKLL-----SAPP 138

                  ....*..
gi 1034572725 371 DSSWRGS 377
Cdd:cd02131   139 SRRKEGS 145

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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1034572725 113 MKAFLDELKaeNIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYD 169
Cdd:cd03874     1 YARKLVDLA--KIKEDLEYLSSMPHMAGTKGDAALAKYIENSFKNNGLFEVELEEYS 55

M28 Zn-peptidase Streptomyces griseus aminopeptidase and similar proteins; Peptidase family M28; Streptomyces griseus Aminopeptidase (SGAP, Leucine aminopeptidase (LAP), aminopeptidase S, Mername-AA022 peptidase) subfamily. SGAP is a di-zinc exopeptidase with high preference towards large hydrophobic amino-terminal residues, with Leu being the most efficiently cleaved. It can accommodate all except Pro and Glu residues in the P1' position. It is a monomeric (30 kDa), calcium-activated and calcium-stabilized enzyme; its activation by calcium correlates with substrate specificity and it has thermal stability only in the presence of calcium. Although SGAP contains a calcium binding site, it is not conserved in many members of this subfamily. SGAP is present in the extracellular fluid of S. griseus cultures.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 389 TGNFSTQKVKMhihsTNEVTRIYNVIGTLRGAvEPDRYVILGGHRDSWVFG-GI-DPQSGAAVVHEIvrsFGTLKKegWR 466
Cdd:cd03876    46 AGYYDVTLQPF----TSLYRTTYNVIAETKGG-DPNNVVMLGAHLDSVSAGpGInDNGSGSAALLEV---ALALAK--FK 115

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1034572725 467 PRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNY 515
Cdd:cd03876   116 VKNAVRFAWWTAEEFGLLGSKFYVNNLSSEERSKIRLYLNFDMIASPNY 164

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 1034572725 411 YNVIGTLRGAVEPDRYVILGGHRDS---WVF------GGIDPQSGAAVVHEIVRsfgTLKKEGWRPRRTILFASWDAEEF 481
Cdd:cd03879    75 PSIIATIPGSEKSDEIVVIGAHQDSingSNPsngrapGADDDGSGTVTILEALR---VLLESGFQPKNTIEFHWYAAEEG 151

                  ....*
gi 1034572725 482 GLLGS 486
Cdd:cd03879   152 GLLGS 156

M28 Zn-peptidase Endoplasmic reticulum metallopeptidase 1; Peptidase family M28; Endoplasmic reticulum metallopeptidase 1 (ERMP1; Felix-ina, FXNA or Fxna peptidase; KIAA1815) subfamily. ERMP1 is a multi-pass membrane protein located in the endoplasmic reticulum membrane. In humans, Fxna may play a crucial role in processing proteins required for the organization of somatic cells and oocytes into discrete follicular structures, although which proteins are hydrolyzed has not yet been determined. Another member of this subfamily is the 24-kDa vacuolar protein (VP24) which is probably involved in the formation of intravacuolar pigmented globules (cyanoplasts) in highly anthocyanin-containing vacuoles; however, the biological function of the C-terminal region which includes the putative transmembrane metallopeptidase domain is unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034572725 400 HIHSTNEVTRIY----NVIGTLRGAV-EPDRYVILGGHRDSWV--FGGIDPQSGAAVVHEIVRSFgtlKKEGWRPRRTIL 472
Cdd:cd03875    65 FNFLSSGMTLVYfevtNIVVRISGKNsNSLPALLLNAHFDSVPtsPGATDDGMGVAVMLEVLRYL---SKSGHQPKRDII 141

                          90
                  ....*....|....
gi 1034572725 473 FASWDAEEFGLLGS 486
Cdd:cd03875   142 FLFNGAEENGLLGA 155

PA_C5a_like: Protease-associated domain containing proteins like Streptococcus pyogenes C5a peptidase. This group contains various PA domain-containing proteins similar to S. pyogenes C5a, including, i) Vpr, a minor extracellular serine protease from Bacillus subtilis, ii) a large molecular mass collagenolytic protease from Geobacillus collagenovorans MO-1, and iii) PrtS, a cell envelope protease from Streptococcus thermophilus CNRZ 385. Proteins in this group belong to the peptidase S8 family. C5a peptidase is a cell surface serine protease which specifically inactivates C5a [a chemotactic peptide, which attracts polymorphonuclear leukocytes (PMNs)], by cleaving it to release a 7-residue carboxy-terminal fragment which contains the PMN binding site. 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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1034572725 228 DLVYVNYARTEDFFKLerDMKincsGKIV-IARyGKVFRGNKVKNAQLAGAKGVILY 283
Cdd:cd02133    29 ELVDAGLGTPEDFEGK--DVK----GKIAlIQR-GEITFVEKIANAKAAGAVGVIIY 78

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 1034572725 412 NVIGTLRGAVEPDRYVILGGHRD------SWVFGGIDPQ-SGAAVVHEIVRSFgtlKKEgwRPRRTILFASWDAEEFGLL 484
Cdd:cd05662    64 NVLAVIKGSEPPTKWRVVSAHYDhlgirgGKIYNGADDNaSGVAALLALAEYF---KKH--PPKHNVIFAATDAEEPGLR 138

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1034572725 485 GSTEWAEENSRLLQERGVAyINAD----SSIEGNYTLRVDCTPLMYSLV--HNLTKELKSPDEGFEGKSLYESWTKKS 556
Cdd:cd05662   139 GSYAFVEALKVPRAQIELN-INLDmisrPERNELYVEGASQFPQLTSILenVKGTCIKALHPKDTDGSIGSIDWTRAS 215

M20 family peptidase;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1034572725 460 LKKEGWRPRRTILFASWDAEEFGLLGstewAEENSRLLQERGV 502
Cdd:PRK08262  169 LLAQGFQPRRTIYLAFGHDEEVGGLG----ARAIAELLKERGV 207