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 301500666 339 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 418
Cdd:cd08022   59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 419 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 498
Cdd:cd08022  139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 499 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 578
Cdd:cd08022  210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                 ..
gi 301500666 579 PF 580
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 301500666  612 VSFDSLFSAVKNFTEIASKFSE---------------------RLQDFDKS-------------KHVIYAPSSHNKYAGE 657
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAwakkwedikepdllavravndKLMLFERAfldpeglpgrpwfKHVVFAPGLWTGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 301500666  658 SFPGIYDALFDieskvdpsKAWGEVKRQIYVAAFTVQAAAETLS 701
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 301500666 339 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 418
Cdd:cd08022   59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 419 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 498
Cdd:cd08022  139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 499 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 578
Cdd:cd08022  210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                 ..
gi 301500666 579 PF 580
Cdd:cd08022  286 PF 287

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 301500666 295 GGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILGGHRDSWVFGG---I 371
Cdd:COG2234    1 ALAAAGGGGGTTAGAAAAAAAAAAAAAGLALLKLKGLLLEAAGGDSRNVIAEIPGTDPPDEVVVLGAHYDSVGSIGpgaD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 372 DPQSGAAVVHEIVRsfgTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAeENSRLLQERGVAYINADSSIEGNYTLRVDC 451
Cdd:COG2234   81 DNASGVAALLELAR---ALAALGPKPKRTIRFVAFGAEEQGLLGSRYYA-ENLKAPLEKIVAVLNLDMIGRGGPRNYLYV 156

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 452 TPLMYSLvhnltkelkspdegfEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRlGIASGrarytkNWETNKF 531
Cdd:COG2234  157 DGDGGSP---------------ELADLLEAAAKAYLPGLGVDPPEETGGYGRSDHAPFAKA-GIPAL------FLFTGAE 214

                        250       260       270       280
                 ....*....|....*....|....*....|....*....|....
gi 301500666 532 SGYPLYHSVYETYELVEkfydpmFKYHLTVAQVRGGMVFELANS 575
Cdd:COG2234  215 DYHPDYHTPSDTLDKID------LDALAKVAQLLAALVYELANA 252

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 301500666  156 EGDLVYVNYARTEDFFKLERDMKincsGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAP----GVKSYPDGW 231
Cdd:pfam02225   1 TGPLVLAPGCYAGDGIPADFDVK----GKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPpgagGNELYPDGI 76

                          90
                  ....*....|....*
gi 301500666  232 NLPGGGVQRGNILNL 246
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 301500666  43 MKAFLDELKaeNIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYD 99
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 301500666 182 SGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSD 215
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 301500666 339 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTE 418
Cdd:cd08022   59 PIWNVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTE 138

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 419 WAEENSRLLQERGVAYINADSSIEGnYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLyeswtkksPSPEFSGMPRIS 498
Cdd:cd08022  139 WVEENADWLQERAVAYLNVDVAVSG-STLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIG 209

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 499 KLGSGNDFEVFFQRLGIASGRARYTKNWEtnkfSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVL 578
Cdd:cd08022  210 NLGSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPIL 285

                 ..
gi 301500666 579 PF 580
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 301500666 321 NFSTQKVKMHIHStnevtRIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTL-KKEGWRPRR 399
Cdd:cd03874   43 NNGLFEVELEEYS-----PITNVVGKIEGIEQPDRAIIIGAHRDSWGYGAGYPNSGTAVLLEIARLFQQLkKKFGWKPLR 117

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 400 TILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEgfegksly 479
Cdd:cd03874  118 TIYFISWDGSEFGLAGSTELGEDRKASLKDEVYAYINIDQLVIGNSELDVDAHPLLQSLFRKASKKVKFPGN-------- 189

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 480 ESWTKKSPspefsgMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWetnkfSGYPLYHSVYETYELVEKFYDPMFKYHL 559
Cdd:cd03874  190 EDWWKHSP------NAKVSNLHQYGDWTPFLNHLGIPVAVFSFKNDR-----NASYPINSSYDTFEWLEKFLDPDFELHS 258

                        250       260
                 ....*....|....*....|
gi 301500666 560 TVAQVRGGMVFELANSIVLP 579
Cdd:cd03874  259 TLAEFVGLLVLSLAEDPLLP 278

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 301500666 295 GGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILGGHRDSWVFGG---I 371
Cdd:COG2234    1 ALAAAGGGGGTTAGAAAAAAAAAAAAAGLALLKLKGLLLEAAGGDSRNVIAEIPGTDPPDEVVVLGAHYDSVGSIGpgaD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 372 DPQSGAAVVHEIVRsfgTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAeENSRLLQERGVAYINADSSIEGNYTLRVDC 451
Cdd:COG2234   81 DNASGVAALLELAR---ALAALGPKPKRTIRFVAFGAEEQGLLGSRYYA-ENLKAPLEKIVAVLNLDMIGRGGPRNYLYV 156

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 452 TPLMYSLvhnltkelkspdegfEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRlGIASGrarytkNWETNKF 531
Cdd:COG2234  157 DGDGGSP---------------ELADLLEAAAKAYLPGLGVDPPEETGGYGRSDHAPFAKA-GIPAL------FLFTGAE 214

                        250       260       270       280
                 ....*....|....*....|....*....|....*....|....
gi 301500666 532 SGYPLYHSVYETYELVEkfydpmFKYHLTVAQVRGGMVFELANS 575
Cdd:COG2234  215 DYHPDYHTPSDTLDKID------LDALAKVAQLLAALVYELANA 252

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 301500666 340 IYNVIGTLRGAVEPDRYVILGGHRDSWVF--GGIDPQSGAAVVHEIVRSFGTLKKegwRPRRTILFASWDAEEFGLLGST 417
Cdd:cd02690    1 GYNVIATIKGSDKPDEVILIGAHYDSVPLspGANDNASGVAVLLELARVLSKLQL---KPKRSIRFAFWDAEELGLLGSK 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 418 EWAEENSRLLQeRGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEgfegkslyeswtkkspSPEFSGMPRI 497
Cdd:cd02690   78 YYAEQLLSSLK-NIRAALNLDMIGGAGPDLYLQTAPGNDALVEKLLRALAHELE----------------NVVYTVVYKE 140

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*...
gi 301500666 498 SKLGSGNDFEVfFQRLGIASGRARytknweTNKFSGYPLYHSVYETYE 545
Cdd:cd02690  141 DGGTGGSDHRP-FLARGIPAASLI------QSESYNFPYYHTTQDTLE 181

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 301500666  156 EGDLVYVNYARTEDFFKLERDMKincsGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAP----GVKSYPDGW 231
Cdd:pfam02225   1 TGPLVLAPGCYAGDGIPADFDVK----GKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPpgagGNELYPDGI 76

                          90
                  ....*....|....*
gi 301500666  232 NLPGGGVQRGNILNL 246
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 301500666 140 SDIVPPFSAFSPQGMPEGDLVYVNYARTEDFfklerdmKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADy 219
Cdd:cd00538   11 GSALLFNPPSSPVGVVAGPLVGCGYGTTDDS-------GADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAVIIYNNGDD- 82

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 301500666 220 fapgvksypdgwnlpgGGVQRGNilnlngagdpltpgypaneyayrrgIAEAVGLPSIPVHPIGYYDAQKLLEKMGGS 297
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 301500666 326 KVKMHIHSTNEVTRiYNVIGTLRGAVEPDRYVILGGHRDSWVF--GGIDPQSGAAVVHEIVRSfgtLKKEGWRPRRTILF 403
Cdd:cd03883  213 ELKMEAKTYPDATS-RNVIAEITGSKYPDEVVLVGGHLDSWDVgtGAMDDGGGVAISWEALKL---IKDLGLKPKRTIRV 288

                         90       100
                 ....*....|....*....|.
gi 301500666 404 ASWDAEEFGLLGSTEWAEENS 424
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 301500666 315 GPGFTGNFsTQKVKMhIHSTNEVTRiYNVIGTLRGAVEPDRYVILGGHRDSW----------VF-GGIDPQSGAAVVHEI 383
Cdd:cd05660   37 PAGSDGSY-LQAVPL-VSKIEYSTS-HNVVAILPGSKLPDEYIVLSAHWDHLgigppiggdeIYnGAVDNASGVAAVLEL 113

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 301500666 384 VRSFgtlKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLqERGVAYINADS 439
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 301500666  43 MKAFLDELKaeNIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYD 99
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 301500666 319 TGNFSTQKVKMhihsTNEVTRIYNVIGTLRGAvEPDRYVILGGHRDSWVFG-GI-DPQSGAAVVHEIvrsFGTLKKegWR 396
Cdd:cd03876   46 AGYYDVTLQPF----TSLYRTTYNVIAETKGG-DPNNVVMLGAHLDSVSAGpGInDNGSGSAALLEV---ALALAK--FK 115

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 301500666 397 PRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNY 445
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 301500666 341 YNVIGTLRGAVEPDRYVILGGHRDS---WVF------GGIDPQSGAAVVHEIVRsfgTLKKEGWRPRRTILFASWDAEEF 411
Cdd:cd03879   75 PSIIATIPGSEKSDEIVVIGAHQDSingSNPsngrapGADDDGSGTVTILEALR---VLLESGFQPKNTIEFHWYAAEEG 151

                 ....*
gi 301500666 412 GLLGS 416
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 301500666 330 HIHSTNEVTRIY----NVIGTLRGAV-EPDRYVILGGHRDSWV--FGGIDPQSGAAVVHEIVRSFgtlKKEGWRPRRTIL 402
Cdd:cd03875   65 FNFLSSGMTLVYfevtNIVVRISGKNsNSLPALLLNAHFDSVPtsPGATDDGMGVAVMLEVLRYL---SKSGHQPKRDII 141

                         90
                 ....*....|....
gi 301500666 403 FASWDAEEFGLLGS 416
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 301500666 158 DLVYVNYARTEDFFKLerDMKincsGKIVIARYGKVFRGNKVKNAQLAGAKGVILY 213
Cdd:cd02133   29 ELVDAGLGTPEDFEGK--DVK----GKIALIQRGEITFVEKIANAKAAGAVGVIIY 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 301500666 342 NVIGTLRGAVEPDRYVILGGHRD------SWVFGGIDPQ-SGAAVVHEIVRSFgtlKKEgwRPRRTILFASWDAEEFGLL 414
Cdd:cd05662   64 NVLAVIKGSEPPTKWRVVSAHYDhlgirgGKIYNGADDNaSGVAALLALAEYF---KKH--PPKHNVIFAATDAEEPGLR 138

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 301500666 415 GSTEWAEENSRLLQERGVAyINAD----SSIEGNYTLRVDCTPLMYSLV--HNLTKELKSPDEGFEGKSLYESWTKKS 486
Cdd:cd05662  139 GSYAFVEALKVPRAQIELN-INLDmisrPERNELYVEGASQFPQLTSILenVKGTCIKALHPKDTDGSIGSIDWTRAS 215

allantoate amidohydrolase; Reviewed

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 301500666 339 RIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGI-DPQSGAAVVHEIVRsfgTLKKEGWRPRRTILFASWDAEE---FG-- 412
Cdd:PRK12890  59 AAGNLFGRLPGRDPDLPPLMTGSHLDTVPNGGRyDGILGVLAGLEVVA---ALREAGIRPPHPLEVIAFTNEEgvrFGps 135

                 ....
gi 301500666 413 LLGS 416
Cdd:PRK12890 136 MIGS 139

PA_subtilisin_like: Protease-associated domain containing subtilisin-like proteases. This group contains various PA domain-containing subtilisin-like proteases including melon cucumisin, Arabidopsis thaliana Ara12, a nodule specific serine protease from Alnus glutinosa ag12, members of the tomato P69 family, and tomato LeSBT2. These proteins belong to the peptidase S8 family. Cucumisin from the juice of melon fruits is a thermostable serine peptidase, with a broad substrate specificity for oligopeptides and proteins. A. thaliana Ara12 is a thermostable, extracellular serine protease, found chiefly in silique tissue and stem tissue. Ara12 is stimulated by Ca2+ ions. A. glutinosa ag12 is expressed at high levels in the nodules, and at low levels in the shoot tips; it is implicated in both symbiotic and non-symbiotic processes in plant development. The tomato P69 protease family is comprised of various protein isoforms of approximately 69KDa. These isoforms accumulate extracellularly. Some of the P69 genes are tightly regulated in a tissue specific fashion, and by environmental and developmental signals. For example: infection with avirulent bacteria activates transcription of the genes for the P69 B and C isoforms, the P69 E transcript was detected only in roots, and the P69F transcript only in hydathodes. The Tomato LeSBT2 subtilase transcript was not detected in flowers and roots, but was present in cotyledons and leaves. 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
                 ....*....|....*....|....*....|....*...
gi 301500666 182 SGKIVIARYGK-VFRGNKVKNAQLAGAKGVILYSDPAD 218
Cdd:cd02120   51 KGKIVLCDRGGnTSRVAKGDAVKAAGGAGMILANDPTD 88