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 2462524112 297 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 376
Cdd:cd08022    59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 377 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 456
Cdd:cd08022   139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 457 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 536
Cdd:cd08022   210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                  ..
gi 2462524112 537 PF 538
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 2462524112 570 VSFDSLFSAVKNFTEIASKFSER---LQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGE 646
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWakkWEDIKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2462524112 647 SFPGIYDALFDieskvdpsKAWGEVKRQIYVAAFTVQAAAETLS 690
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 2462524112 297 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 376
Cdd:cd08022    59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 377 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 456
Cdd:cd08022   139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 457 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 536
Cdd:cd08022   210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                  ..
gi 2462524112 537 PF 538
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 2462524112 570 VSFDSLFSAVKNFTEIASKFSER---LQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGE 646
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWakkWEDIKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2462524112 647 SFPGIYDALFDieskvdpsKAWGEVKRQIYVAAFTVQAAAETLS 690
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 2462524112 114 EGDLVYVNYARTEDFFKLERDMKincsGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAP----GVKSYPDGW 189
Cdd:pfam02225   1 TGPLVLAPGCYAGDGIPADFDVK----GKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPpgagGNELYPDGI 76

                          90
                  ....*....|....*
gi 2462524112 190 NLPGGGVQRGNILNL 204
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 2462524112   1 MKAFLDELKaeNIKKFLHNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYD 57
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 2462524112 140 SGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSD 173
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 2462524112 297 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 376
Cdd:cd08022    59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 377 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 456
Cdd:cd08022   139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 457 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 536
Cdd:cd08022   210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                  ..
gi 2462524112 537 PF 538
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 2462524112 279 NFSTQKVKMHIHStnevtRIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTL-KKEGWRPRR 357
Cdd:cd03874    43 NNGLFEVELEEYS-----PITNVVGKIEGIEQPDRAIIIGAHRDSWGYGAGYPNSGTAVLLEIARLFQQLkKKFGWKPLR 117

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 358 TILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEgfegksly 437
Cdd:cd03874   118 TIYFISWDGSEFGLAGSTELGEDRKASLKDEVYAYINIDQLVIGNSELDVDAHPLLQSLFRKASKKVKFPGN-------- 189

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 438 ESWTKKSPspefsgMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWetnkfSGYPLYHSVYETYELVEKFYDPMFKYHL 517
Cdd:cd03874   190 EDWWKHSP------NAKVSNLHQYGDWTPFLNHLGIPVAVFSFKNDR-----NASYPINSSYDTFEWLEKFLDPDFELHS 258

                         250       260
                  ....*....|....*....|
gi 2462524112 518 TVAQVRGGMVFELANSIVLP 537
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 2462524112 570 VSFDSLFSAVKNFTEIASKFSER---LQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGE 646
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWakkWEDIKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2462524112 647 SFPGIYDALFDieskvdpsKAWGEVKRQIYVAAFTVQAAAETLS 690
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 2462524112 103 PFSAFSPQGMPEGDLVYVNYARTEDFFKLeRDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYfaPGV 182
Cdd:cd02128    19 GYVAYSAAGTVTGKLVYANYGRKKDFEDL-QSVGVSVNGSVVLVRAGKISFAEKVANAEKLGAVGVLIYPDPADF--PID 95

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 183 KSYpdgwNLPGGGVQRgnilnlnGAGDPLTPGYPA-NEYAYRRgiAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPdSS 261
Cdd:cd02128    96 PSE----TALFGHVHL-------GTGDPYTPGFPSfNHTQFPP--SQSSGLPNIPAQTISAAAAAKLLSKMGGPVCP-SG 161

                         170       180
                  ....*....|....*....|....*...
gi 2462524112 262 WRGSLkVPYNVGPGftgnfSTQKVKMHI 289
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 2462524112 114 EGDLVYVNYARTEDFFKLERDMKincsGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAP----GVKSYPDGW 189
Cdd:pfam02225   1 TGPLVLAPGCYAGDGIPADFDVK----GKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPpgagGNELYPDGI 76

                          90
                  ....*....|....*
gi 2462524112 190 NLPGGGVQRGNILNL 204
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 2462524112  98 SDIVPPFSAFSPQGMPEGDLVYVNYARTEDFfklerdmKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADy 177
Cdd:cd00538    11 GSALLFNPPSSPVGVVAGPLVGCGYGTTDDS-------GADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAVIIYNNGDD- 82

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2462524112 178 fapgvksypdgwnlpgGGVQRGNilnlngagdpltpgypaneyayrrgIAEAVGLPSIPVHPIGYYDAQKLLEKMGGS 255
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 2462524112 284 KVKMHIHSTNEVTRiYNVIGTLRGAVEPDRYVILGGHRDSWVF--GGIDPQSGAAVVHEIVRSfgtLKKEGWRPRRTILF 361
Cdd:cd03883   213 ELKMEAKTYPDATS-RNVIAEITGSKYPDEVVLVGGHLDSWDVgtGAMDDGGGVAISWEALKL---IKDLGLKPKRTIRV 288

                          90       100
                  ....*....|....*....|.
gi 2462524112 362 ASWDAEEFGLLGSTEWAEENS 382
Cdd:cd03883   289 VLWTGEEQGLVGAKAYAEAHK 309

M28 Zn-peptidase containing a protease-associated (PA) domain insert; 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 containing 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 273 GPGFTGNFsTQKVKMhIHSTNEVTRiYNVIGTLRGAVEPDRYVILGGHRDSW----------VF-GGIDPQSGAAVVHEI 341
Cdd:cd05660    37 PAGSDGSY-LQAVPL-VSKIEYSTS-HNVVAILPGSKLPDEYIVLSAHWDHLgigppiggdeIYnGAVDNASGVAAVLEL 113

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462524112 342 VRSFgtlKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLqERGVAYINADS 397
Cdd:cd05660   114 ARVF---AAQDQRPKRSIVFLAVTAEEKGLLGSRYYAANPIFPL-DKIVANLNIDM 165

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 2462524112   1 MKAFLDELKaeNIKKFLHNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYD 57
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 2462524112 277 TGNFSTQKVKMhihsTNEVTRIYNVIGTLRGAvEPDRYVILGGHRDSWVFG-GI-DPQSGAAVVHEIvrsFGTLKKegWR 354
Cdd:cd03876    46 AGYYDVTLQPF----TSLYRTTYNVIAETKGG-DPNNVVMLGAHLDSVSAGpGInDNGSGSAALLEV---ALALAK--FK 115

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 2462524112 355 PRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNY 403
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 2462524112 299 YNVIGTLRGAVEPDRYVILGGHRDS---WVF------GGIDPQSGAAVVHEIVRsfgTLKKEGWRPRRTILFASWDAEEF 369
Cdd:cd03879    75 PSIIATIPGSEKSDEIVVIGAHQDSingSNPsngrapGADDDGSGTVTILEALR---VLLESGFQPKNTIEFHWYAAEEG 151

                  ....*
gi 2462524112 370 GLLGS 374
Cdd:cd03879   152 GLLGS 156

M28 Zn-peptidase containing a PA domain insert; 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 containing 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462524112 299 YNVIGTLR--GAVEPDRYVILGGHRDSWVF--GGIDPQSGAAVVHEIVRSFGTLKKEgwrprRTILFASWDAEEFGLLGS 374
Cdd:cd05661    61 HNVIATKKpdNNKNNNDIIIVTSHYDSVVKapGANDNASGTAVTLELARVFKKVKTD-----KELRFIAFGAEENGLLGS 135

                          90       100
                  ....*....|....*....|..
gi 2462524112 375 TEWAEENSRLLQERGVAYINAD 396
Cdd:cd05661   136 KYYVASLSEDEIKRTIGVFNLD 157

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 2462524112 116 DLVYVNYARTEDFFKLerDMKincsGKIV-IARyGKVFRGNKVKNAQLAGAKGVILY 171
Cdd:cd02133    29 ELVDAGLGTPEDFEGK--DVK----GKIAlIQR-GEITFVEKIANAKAAGAVGVIIY 78

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2462524112 101 VPPFSAF--SPQGMPEGDLVYVNYARTEdffklERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILY-SDPAD 176
Cdd:cd02130     8 AIPTTAFtySPAGEVTGPLVVVPNLGCD-----AADYPASVAGNIALIERGECPFGDKSALAGAAGAAAAIIYnNVPAG 81

M20 family peptidase;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2462524112 348 LKKEGWRPRRTILFASWDAEEFGLLGstewAEENSRLLQERGV 390
Cdd:PRK08262  169 LLAQGFQPRRTIYLAFGHDEEVGGLG----ARAIAELLKERGV 207