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Conserved domains on  [gi|767967355|ref|XP_011543009|]
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aminopeptidase NAALADL1 isoform X2 [Homo sapiens]

Protein Classification

M28 family metallopeptidase( domain architecture ID 10329992)

M28 family metallopeptidase similar to Homo sapiens glutamate carboxypeptidase 2, N-acetylated-alpha-linked acidic dipeptidase 2 and N-acetylated-alpha-linked acidic dipeptidase-like protein

Graphical summary

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List of domain hits

 Name Accession Description Interval E-value
M28_PSMA_like cd08022
M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific ...
 300-539 1.69e-123

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.


:

Pssm-ID: 349942 [Multi-domain]  Cd Length: 287  Bit Score: 368.87  E-value: 1.69e-123
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 300 NVLGIIRGAVEPDRYVLYGNHRDSWVHGAVDPSSGTAVLLELSRVLGTLLKKGtWRPRRSIVFASWGAEEFGLIGSTEFT 379
Cdd:cd08022   62 NVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKG-WRPRRTIIFASWDAEEYGLIGSTEWV 140

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 380 EEFFNKLQERTVAYINVDISVfANATLRVQGTPPVQSVVFSATKEIRSPGPGDLSIYDnwiryfnrSSPVYGLVPSLGSL 459
Cdd:cd08022  141 EENADWLQERAVAYLNVDVAV-SGSTLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIGNL 211

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 460 GAGSDYAPFVHFLGISSMDIAYTYDRSktsaRIYPTYHTAFDTFDYVDKFLDPGFSSHQAVARTAGSVILRLSDSFFLPL 539
Cdd:cd08022  212 GSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPILPF 287
PA_GCPII_like cd02121
PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II ...
 61-287 2.28e-89

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


:

Pssm-ID: 239036  Cd Length: 220  Bit Score: 278.02  E-value: 2.28e-89
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  61 PSQEQPNVVDIVGPTGgiihschRTEENVTG-EQGGPDVVQPYAAYAPSGTPQGLLVYANRGAEEDFKELQTQGIKLEGT 139
Cdd:cd02121    1 PVKRSLILTKPDGATG-------KLIEDTVLeEPPSPDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVKGK 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 140 IALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPADINDGLSSPDETFPNSWYLPPSGVERGSYY---EYFGDPLTPYLPAV 216
Cdd:cd02121   74 IVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENGKTYPDGPARPPSGVQRGSVLfmsIGPGDPLTPGYPSK 153

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967355 217 PSSFRVDLANVSGFPPIPTQPIGFQDARDLLCNLNGTLAPATWQGALGCHYRLGPGfrpdGDFPADSQVNV 287
Cdd:cd02121  154 PGAERRDKEESKGLPKIPSLPISYRDAQPLLKALGGPGAPSDWQGGLPVTYRLGFG----GPSPGKVRVNL 220
TFR_dimer pfam04253
Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the ...
 568-687 7.62e-30

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


:

Pssm-ID: 461238  Cd Length: 116  Bit Score: 113.83  E-value: 7.62e-30
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  568 ISLGPLVTAVEKFEAEAAALGQRISTLQK-GSPDPLQVRMLNDQLMLLERTFLNPRAFPEERYYSHVLWAPR---TGSVV 643
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWAKKWEDiKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGlwtGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 767967355  644 TFPGLSNACSrardtasgSEAWAEVQRQLSIVVTALEGAAATLR 687
Cdd:pfam04253  81 TFPGIRDAIE--------AGDWELAQKQISIVAKAIQSAAETLK 116
Zinc_peptidase_like super family cl14876
Zinc peptidases M18, M20, M28, and M42; Zinc peptidases play vital roles in metabolic and ...
 1-73 1.17e-11

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


The actual alignment was detected with superfamily member cd08022:

Pssm-ID: 472712 [Multi-domain]  Cd Length: 287  Bit Score: 66.10  E-value: 1.17e-11
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767967355   1 MGQLDAHRIRENLRELSREPHLASSPRDEDLVQLLLQRWKDPesGLDSAEASTYEVLL-----SFPSQEQPNVVDIVG 73
Cdd:cd08022    5 LDEPDAENIREWLRYYTSGPHLAGTEGNLELAQWTEDKWREF--GLDDVELEEYDVPIwnvigTIRGSEEPDEYIILG 80
 
Name Accession Description Interval E-value
M28_PSMA_like cd08022
M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific ...
 300-539 1.69e-123

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.


Pssm-ID: 349942 [Multi-domain]  Cd Length: 287  Bit Score: 368.87  E-value: 1.69e-123
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 300 NVLGIIRGAVEPDRYVLYGNHRDSWVHGAVDPSSGTAVLLELSRVLGTLLKKGtWRPRRSIVFASWGAEEFGLIGSTEFT 379
Cdd:cd08022   62 NVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKG-WRPRRTIIFASWDAEEYGLIGSTEWV 140

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 380 EEFFNKLQERTVAYINVDISVfANATLRVQGTPPVQSVVFSATKEIRSPGPGDLSIYDnwiryfnrSSPVYGLVPSLGSL 459
Cdd:cd08022  141 EENADWLQERAVAYLNVDVAV-SGSTLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIGNL 211

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 460 GAGSDYAPFVHFLGISSMDIAYTYDRSktsaRIYPTYHTAFDTFDYVDKFLDPGFSSHQAVARTAGSVILRLSDSFFLPL 539
Cdd:cd08022  212 GSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPILPF 287
PA_GCPII_like cd02121
PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II ...
 61-287 2.28e-89

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


Pssm-ID: 239036  Cd Length: 220  Bit Score: 278.02  E-value: 2.28e-89
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  61 PSQEQPNVVDIVGPTGgiihschRTEENVTG-EQGGPDVVQPYAAYAPSGTPQGLLVYANRGAEEDFKELQTQGIKLEGT 139
Cdd:cd02121    1 PVKRSLILTKPDGATG-------KLIEDTVLeEPPSPDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVKGK 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 140 IALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPADINDGLSSPDETFPNSWYLPPSGVERGSYY---EYFGDPLTPYLPAV 216
Cdd:cd02121   74 IVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENGKTYPDGPARPPSGVQRGSVLfmsIGPGDPLTPGYPSK 153

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967355 217 PSSFRVDLANVSGFPPIPTQPIGFQDARDLLCNLNGTLAPATWQGALGCHYRLGPGfrpdGDFPADSQVNV 287
Cdd:cd02121  154 PGAERRDKEESKGLPKIPSLPISYRDAQPLLKALGGPGAPSDWQGGLPVTYRLGFG----GPSPGKVRVNL 220
Iap COG2234
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein ...
 295-534 3.17e-38

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


Pssm-ID: 441835 [Multi-domain]  Cd Length: 257  Bit Score: 142.58  E-value: 3.17e-38
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 295 LRNSSNVLGIIRGAVEPDRYVLYGNHRDSWVH---GAVDPSSGTAVLLELSRVLgtllKKGTWRPRRSIVFASWGAEEFG 371
Cdd:COG2234   43 GGDSRNVIAEIPGTDPPDEVVVLGAHYDSVGSigpGADDNASGVAALLELARAL----AALGPKPKRTIRFVAFGAEEQG 118

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 372 LIGSTEFTEEFFNKLqERTVAYINVDISVFANATLRVqgtppvqsvvfsaTKEIRSPGPGDLSIYDNWIRYFNRSSPVYg 451
Cdd:COG2234  119 LLGSRYYAENLKAPL-EKIVAVLNLDMIGRGGPRNYL-------------YVDGDGGSPELADLLEAAAKAYLPGLGVD- 183

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 452 lVPSLGSLGAGSDYAPFVHfLGISSMDIAYTYDrsktsaRIYPTYHTAFDTFDYVDkfldpgFSSHQAVARTAGSVILRL 531
Cdd:COG2234  184 -PPEETGGYGRSDHAPFAK-AGIPALFLFTGAE------DYHPDYHTPSDTLDKID------LDALAKVAQLLAALVYEL 249


                 ...
gi 767967355 532 SDS 534
Cdd:COG2234  250 ANA 252
TFR_dimer pfam04253
Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the ...
 568-687 7.62e-30

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


Pssm-ID: 461238  Cd Length: 116  Bit Score: 113.83  E-value: 7.62e-30
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  568 ISLGPLVTAVEKFEAEAAALGQRISTLQK-GSPDPLQVRMLNDQLMLLERTFLNPRAFPEERYYSHVLWAPR---TGSVV 643
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWAKKWEDiKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGlwtGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 767967355  644 TFPGLSNACSrardtasgSEAWAEVQRQLSIVVTALEGAAATLR 687
Cdd:pfam04253  81 TFPGIRDAIE--------AGDWELAQKQISIVAKAIQSAAETLK 116
Peptidase_M28 pfam04389
Peptidase family M28;
300-508 4.50e-29

Peptidase family M28;


Pssm-ID: 461288 [Multi-domain]  Cd Length: 192  Bit Score: 114.30  E-value: 4.50e-29
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  300 NVLGIIRGAvEPDRYVLYGNHRDSWVH--GAVDPSSGTAVLLELSRVLGTLlkkgtWRPRRSIVFASWGAEEFGLIGSTE 377
Cdd:pfam04389   1 NVIAKLPGK-APDEVVLLSAHYDSVGTgpGADDNASGVAALLELARVLAAG-----QRPKRSVRFLFFDAEEAGLLGSHH 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  378 FTEEffNKLQERTVAYINVDISVFANATLRVQgtppvqsvvfsatkeirSPGPGDLSIYDNWIRYFNRSSPVYGLVPSLG 457
Cdd:pfam04389  75 FAKS--HPPLKKIRAVINLDMIGSGGPALLFQ-----------------SGPKGSSLLEKYLKAAAKPYGVTLAEDPFQE 135

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 767967355  458 SLGAG-SDYAPFVHfLGISSMDIAYTYDRsktsariyPTYHTAFDTFDYVDK 508
Cdd:pfam04389 136 RGGPGrSDHAPFIK-AGIPGLDLAFTDFG--------YRYHTPADTIDNIDP 178
M28_PSMA_like cd08022
M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific ...
 1-73 1.17e-11

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.


Pssm-ID: 349942 [Multi-domain]  Cd Length: 287  Bit Score: 66.10  E-value: 1.17e-11
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767967355   1 MGQLDAHRIRENLRELSREPHLASSPRDEDLVQLLLQRWKDPesGLDSAEASTYEVLL-----SFPSQEQPNVVDIVG 73
Cdd:cd08022    5 LDEPDAENIREWLRYYTSGPHLAGTEGNLELAQWTEDKWREF--GLDDVELEEYDVPIwnvigTIRGSEEPDEYIILG 80
PA pfam02225
PA domain; The PA (Protease associated) domain is found as an insert domain in diverse ...
 112-200 1.42e-10

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.


Pssm-ID: 460499 [Multi-domain]  Cd Length: 91  Bit Score: 58.29  E-value: 1.42e-10
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  112 QGLLVYANRGAEEDFkelQTQGIKLEGTIALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPAD-INDGLSSPDETFPNSWY 190
Cdd:pfam02225   1 TGPLVLAPGCYAGDG---IPADFDVKGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGlGGPPGAGGNELYPDGIY 77

                          90
                  ....*....|
gi 767967355  191 LPPSGVERGS 200
Cdd:pfam02225  78 IPAVGVSRAD 87
 
Name Accession Description Interval E-value
M28_PSMA_like cd08022
M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific ...
 300-539 1.69e-123

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.


Pssm-ID: 349942 [Multi-domain]  Cd Length: 287  Bit Score: 368.87  E-value: 1.69e-123
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 300 NVLGIIRGAVEPDRYVLYGNHRDSWVHGAVDPSSGTAVLLELSRVLGTLLKKGtWRPRRSIVFASWGAEEFGLIGSTEFT 379
Cdd:cd08022   62 NVIGTIRGSEEPDEYIILGNHRDAWVFGAGDPNSGTAVLLEVARALGTLLKKG-WRPRRTIIFASWDAEEYGLIGSTEWV 140

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 380 EEFFNKLQERTVAYINVDISVfANATLRVQGTPPVQSVVFSATKEIRSPGPGDLSIYDnwiryfnrSSPVYGLVPSLGSL 459
Cdd:cd08022  141 EENADWLQERAVAYLNVDVAV-SGSTLRAAGSPLLQNLLREAAKEVQDPDEGATLKYL--------PSWWDDTGGEIGNL 211

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 460 GAGSDYAPFVHFLGISSMDIAYTYDRSktsaRIYPTYHTAFDTFDYVDKFLDPGFSSHQAVARTAGSVILRLSDSFFLPL 539
Cdd:cd08022  212 GSGSDYTPFLDHLGIASIDFGFSGGPT----DPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPILPF 287
PA_GCPII_like cd02121
PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II ...
 61-287 2.28e-89

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


Pssm-ID: 239036  Cd Length: 220  Bit Score: 278.02  E-value: 2.28e-89
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  61 PSQEQPNVVDIVGPTGgiihschRTEENVTG-EQGGPDVVQPYAAYAPSGTPQGLLVYANRGAEEDFKELQTQGIKLEGT 139
Cdd:cd02121    1 PVKRSLILTKPDGATG-------KLIEDTVLeEPPSPDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVKGK 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 140 IALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPADINDGLSSPDETFPNSWYLPPSGVERGSYY---EYFGDPLTPYLPAV 216
Cdd:cd02121   74 IVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENGKTYPDGPARPPSGVQRGSVLfmsIGPGDPLTPGYPSK 153

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967355 217 PSSFRVDLANVSGFPPIPTQPIGFQDARDLLCNLNGTLAPATWQGALGCHYRLGPGfrpdGDFPADSQVNV 287
Cdd:cd02121  154 PGAERRDKEESKGLPKIPSLPISYRDAQPLLKALGGPGAPSDWQGGLPVTYRLGFG----GPSPGKVRVNL 220
M28_PMSA_TfR_like cd03874
M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor ...
 300-538 1.99e-68

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.


Pssm-ID: 349871 [Multi-domain]  Cd Length: 278  Bit Score: 225.25  E-value: 1.99e-68
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 300 NVLGIIRGAVEPDRYVLYGNHRDSWVHGAVDPSSGTAVLLELSRVLGTLLKKGTWRPRRSIVFASWGAEEFGLIGSTEFT 379
Cdd:cd03874   59 NVVGKIEGIEQPDRAIIIGAHRDSWGYGAGYPNSGTAVLLEIARLFQQLKKKFGWKPLRTIYFISWDGSEFGLAGSTELG 138

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 380 EEFFNKLQERTVAYINVDISVFANATLRVQGTPPVQSVVFSATKEIRSPGPGDLSIYDNWIRyfnrsspvyglVPSLGSl 459
Cdd:cd03874  139 EDRKASLKDEVYAYINIDQLVIGNSELDVDAHPLLQSLFRKASKKVKFPGNEDWWKHSPNAK-----------VSNLHQ- 206

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 767967355 460 gaGSDYAPFVHFLGISSMDIAYTYDRSktsaRIYPtYHTAFDTFDYVDKFLDPGFSSHQAVARTAGSVILRLSDSFFLP 538
Cdd:cd03874  207 --YGDWTPFLNHLGIPVAVFSFKNDRN----ASYP-INSSYDTFEWLEKFLDPDFELHSTLAEFVGLLVLSLAEDPLLP 278
M28_TfR cd09848
M28 Zn-peptidase Transferrin Receptor family; Peptidase M28 family; Transferrin Receptor (TfR) ...
 299-539 1.58e-49

M28 Zn-peptidase Transferrin Receptor family; Peptidase M28 family; Transferrin Receptor (TfR) subfamily. TfRs 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). While related in sequence to peptidase M28 glutamate carboxypeptidase II (also called prostate-specific membrane antigen or PSMA), TfR lacks the metal ion coordination centers and protease activity of that group.


Pssm-ID: 349946 [Multi-domain]  Cd Length: 285  Bit Score: 174.87  E-value: 1.58e-49
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 299 SNVLGIIRGAVEPDRYVLYGNHRDSWVHGAVDPSSGTAVLLELSRVLGTLLKKGTWRPRRSIVFASWGAEEFGLIGSTEF 378
Cdd:cd09848   57 HNIFGVIKGFVEPDRYVVIGAQRDAWGPGAAKSGVGTALLLELARTFSDMVKNDGFKPRRSIVFASWSAGDFGSVGATEW 136

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 379 TEEFFNKLQERTVAYINVDISVFANATLRVQGTPPVQSVVFSATKEIRSPGPGDLSIYDNwiryfNRSSPVYGLVPslgs 458
Cdd:cd09848  137 LEGYLSSLHLKAFTYISLDGAVLGDDSFKASASPLLYTLIESTMKQVKSPVHSGQSYYET-----RSSWWASIVEP---- 207

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 459 LGAGSDYAPFVHFLGISSMDIAYTYDRsktsaRIYPTYHTAFDTFDYVDKFLDPGFSS-HQAVARTAGSVILRLSDSFFL 537
Cdd:cd09848  208 LGLDSAAYPFLAFSGIPSVSFHFTEDD-----EDYPFLGTKEDTKENLDKFTNGELWEvAAAAAEVAGQMALRLVHDHLL 282


                 ..
gi 767967355 538 PL 539
Cdd:cd09848  283 PL 284
Iap COG2234
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein ...
 295-534 3.17e-38

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


Pssm-ID: 441835 [Multi-domain]  Cd Length: 257  Bit Score: 142.58  E-value: 3.17e-38
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 295 LRNSSNVLGIIRGAVEPDRYVLYGNHRDSWVH---GAVDPSSGTAVLLELSRVLgtllKKGTWRPRRSIVFASWGAEEFG 371
Cdd:COG2234   43 GGDSRNVIAEIPGTDPPDEVVVLGAHYDSVGSigpGADDNASGVAALLELARAL----AALGPKPKRTIRFVAFGAEEQG 118

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 372 LIGSTEFTEEFFNKLqERTVAYINVDISVFANATLRVqgtppvqsvvfsaTKEIRSPGPGDLSIYDNWIRYFNRSSPVYg 451
Cdd:COG2234  119 LLGSRYYAENLKAPL-EKIVAVLNLDMIGRGGPRNYL-------------YVDGDGGSPELADLLEAAAKAYLPGLGVD- 183

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 452 lVPSLGSLGAGSDYAPFVHfLGISSMDIAYTYDrsktsaRIYPTYHTAFDTFDYVDkfldpgFSSHQAVARTAGSVILRL 531
Cdd:COG2234  184 -PPEETGGYGRSDHAPFAK-AGIPALFLFTGAE------DYHPDYHTPSDTLDKID------LDALAKVAQLLAALVYEL 249


                 ...
gi 767967355 532 SDS 534
Cdd:COG2234  250 ANA 252
M28 cd02690
M28 Zn-peptidases include aminopeptidases and carboxypeptidases; Peptidase M28 family (also ...
 298-531 7.49e-31

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.


Pssm-ID: 349868 [Multi-domain]  Cd Length: 202  Bit Score: 119.76  E-value: 7.49e-31
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 298 SSNVLGIIRGAVEPDRYVLYGNHRDSW--VHGAVDPSSGTAVLLELSRVLGTLLKKgtwrPRRSIVFASWGAEEFGLIGS 375
Cdd:cd02690    1 GYNVIATIKGSDKPDEVILIGAHYDSVplSPGANDNASGVAVLLELARVLSKLQLK----PKRSIRFAFWDAEELGLLGS 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 376 TEFTEEFFNKLQeRTVAYINVDISVFANATLRVQGTPPVQSVVFSATKEIRSpgpgdlsiydnwiryfNRSSPVYGLVPS 455
Cdd:cd02690   77 KYYAEQLLSSLK-NIRAALNLDMIGGAGPDLYLQTAPGNDALVEKLLRALAH----------------ELENVVYTVVYK 139

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 767967355 456 LGSLGAGSDYAPFvHFLGISS---MDIAYTYDrsktsariyPTYHTAFDTFDYVDKfldpgfSSHQAVARTAGSVILRL 531
Cdd:cd02690  140 EDGGTGGSDHRPF-LARGIPAaslIQSESYNF---------PYYHTTQDTLENIDK------DTLKRAGDILASFLYRL 202
TFR_dimer pfam04253
Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the ...
 568-687 7.62e-30

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


Pssm-ID: 461238  Cd Length: 116  Bit Score: 113.83  E-value: 7.62e-30
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  568 ISLGPLVTAVEKFEAEAAALGQRISTLQK-GSPDPLQVRMLNDQLMLLERTFLNPRAFPEERYYSHVLWAPR---TGSVV 643
Cdd:pfam04253   1 LSLEPLRKAIEKFKKAAKEFDAWAKKWEDiKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGlwtGYAGA 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 767967355  644 TFPGLSNACSrardtasgSEAWAEVQRQLSIVVTALEGAAATLR 687
Cdd:pfam04253  81 TFPGIRDAIE--------AGDWELAQKQISIVAKAIQSAAETLK 116
Peptidase_M28 pfam04389
Peptidase family M28;
300-508 4.50e-29

Peptidase family M28;


Pssm-ID: 461288 [Multi-domain]  Cd Length: 192  Bit Score: 114.30  E-value: 4.50e-29
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  300 NVLGIIRGAvEPDRYVLYGNHRDSWVH--GAVDPSSGTAVLLELSRVLGTLlkkgtWRPRRSIVFASWGAEEFGLIGSTE 377
Cdd:pfam04389   1 NVIAKLPGK-APDEVVLLSAHYDSVGTgpGADDNASGVAALLELARVLAAG-----QRPKRSVRFLFFDAEEAGLLGSHH 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  378 FTEEffNKLQERTVAYINVDISVFANATLRVQgtppvqsvvfsatkeirSPGPGDLSIYDNWIRYFNRSSPVYGLVPSLG 457
Cdd:pfam04389  75 FAKS--HPPLKKIRAVINLDMIGSGGPALLFQ-----------------SGPKGSSLLEKYLKAAAKPYGVTLAEDPFQE 135

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 767967355  458 SLGAG-SDYAPFVHfLGISSMDIAYTYDRsktsariyPTYHTAFDTFDYVDK 508
Cdd:pfam04389 136 RGGPGrSDHAPFIK-AGIPGLDLAFTDFG--------YRYHTPADTIDNIDP 178
PA_TfR cd02128
PA_TfR: Protease-associated domain containing proteins like transferrin receptor (TfR). This ...
 89-272 1.52e-28

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.


Pssm-ID: 239043 [Multi-domain]  Cd Length: 183  Bit Score: 112.49  E-value: 1.52e-28
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  89 VTGEQGGPDVVQP----YAAYAPSGTPQGLLVYANRGAEEDFKELQTQGIKLEGTIALTRYGGVGRGAKAVNAAKHGVAG 164
Cdd:cd02128    3 IIGDAGRLNELVEnpggYVAYSAAGTVTGKLVYANYGRKKDFEDLQSVGVSVNGSVVLVRAGKISFAEKVANAEKLGAVG 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 165 VLVYTDPADINdglSSPDETfpnswylPPSG-VERGSyyeyfGDPLTPYLPavpsSF---RVDLANVSGFPPIPTQPIGF 240
Cdd:cd02128   83 VLIYPDPADFP---IDPSET-------ALFGhVHLGT-----GDPYTPGFP----SFnhtQFPPSQSSGLPNIPAQTISA 143

                        170       180       190
                 ....*....|....*....|....*....|..
gi 767967355 241 QDARDLLCNLNGTLAPATWQGALGcHYRLGPG 272
Cdd:cd02128  144 AAAAKLLSKMGGPVCPSGWKGGDS-TCRLGTS 174
M28_like_PA cd05660
M28 Zn-peptidase containing a protease-associated (PA) domain insert; Peptidase family M28 ...
 272-397 2.29e-20

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.


Pssm-ID: 349910 [Multi-domain]  Cd Length: 290  Bit Score: 92.04  E-value: 2.29e-20
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 272 GFRPDGDFPADSQvNVSVYNRLELRNSSNVLGIIRGAVEPDRYVLYGNHrdsWVH--------------GAVDPSSGTAV 337
Cdd:cd05660   34 GLKPAGSDGSYLQ-AVPLVSKIEYSTSHNVVAILPGSKLPDEYIVLSAH---WDHlgigppiggdeiynGAVDNASGVAA 109

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 338 LLELSRVLgtllKKGTWRPRRSIVFASWGAEEFGLIGSTEFTEEFFNKLqERTVAYINVD 397
Cdd:cd05660  110 VLELARVF----AAQDQRPKRSIVFLAVTAEEKGLLGSRYYAANPIFPL-DKIVANLNID 164
M28_like cd03877
M28 Zn-peptidase, many containing a protease-associated (PA) domain insert; Peptidase family ...
 298-397 8.42e-19

M28 Zn-peptidase, many 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, many of which contain a protease-associated (PA) domain insert which may participate in substrate binding and/or promote conformational changes, influencing the stability and accessibility of the site to substrate. Some proteins in this subfamily are also associated with the PDZ domain, a widespread protein module that has been recruited to serve multiple functions during the course of evolution.


Pssm-ID: 349874 [Multi-domain]  Cd Length: 206  Bit Score: 85.37  E-value: 8.42e-19
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 298 SSNVLGIIRGAVEPDRYVLYGNHRDswvH--------------GAVDPSSGTAVLLELSRVLgtllkKGTWRPRRSIVFA 363
Cdd:cd03877    1 GHNVVGVLEGSDLPDETIVIGAHYD---HlgigggdsgdkiynGADDNASGVAAVLELARYF-----AKQKTPKRSIVFA 72

                         90       100       110
                 ....*....|....*....|....*....|....
gi 767967355 364 SWGAEEFGLIGSTEFTEEFFNKLqERTVAYINVD 397
Cdd:cd03877   73 AFTAEEKGLLGSKYFAENPKFPL-DKIVAMLNLD 105
M28_like cd08015
M28 Zn-peptidase-like; uncharacterized subfamily; Peptidase family M28 (also called ...
 300-506 2.16e-18

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


Pssm-ID: 349937 [Multi-domain]  Cd Length: 218  Bit Score: 84.57  E-value: 2.16e-18
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 300 NVLGIIRGAVEPDRYVLYGNHRDSW--VHGAVDPSSGTAVLLELSRvlgtLLKKGTWRPRRSIVFASWGAEEFGLIGSTE 377
Cdd:cd08015    3 NVIAEIPGSDKKDEVVILGAHLDSWhgATGATDNGAGTAVMMEAMR----ILKAIGSKPKRTIRVALWGSEEQGLHGSRA 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 378 FTEEFF--------NKLQERTVAYINVDisvfaNATLRVQGTppvqsvvfsATKEIRSPGPgdlsIYDNWIRYFNRSSPV 449
Cdd:cd08015   79 YVEKHFgdpptmqlQRDHKKISAYFNLD-----NGTGRIRGI---------YLQGNLAAYP----IFSAWLYPFHDLGAT 140

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 767967355 450 YGLVPSLGslgaGSDYAPFVHfLGISSMDiaYTYDRSKTSARiypTYHTAFDTFDYV 506
Cdd:cd08015  141 TVIERNTG----GTDHAAFDA-VGIPAFQ--FIQDPWDYWTR---THHTNRDTYDRL 187
M28_Fxna_like cd03875
M28 Zn-peptidase Endoplasmic reticulum metallopeptidase 1; Peptidase family M28; Endoplasmic ...
 274-508 1.59e-17

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.


Pssm-ID: 349872 [Multi-domain]  Cd Length: 307  Bit Score: 83.79  E-value: 1.59e-17
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 274 RPDGDFPADSQVNVSVYnrlelRNSSNVLGIIRGAV-EPDRYVLYGNHRDSWV--HGAVDPSSGTAVLLELSRVlgtlLK 350
Cdd:cd03875   60 TGSGSFNFLSSGMTLVY-----FEVTNIVVRISGKNsNSLPALLLNAHFDSVPtsPGATDDGMGVAVMLEVLRY----LS 130

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 351 KGTWRPRRSIVFASWGAEEFGLIGSTEFTEEffNKLQERTVAYINVDIS-------VFanatlrvQGTPPVQSVVFSAtk 423
Cdd:cd03875  131 KSGHQPKRDIIFLFNGAEENGLLGAHAFITQ--HPWAKNVRAFINLEAAgaggraiLF-------QTGPPWLVEAYYS-- 199

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 424 eiRSPGPGDLSIYDNwirYFNRsspvyGLVPSlgslgaGSDYAPFVHFLGISSMDIAYTYDRSktsariypTYHTAFDTF 503
Cdd:cd03875  200 --AAKHPFASVIAQD---VFQS-----GLIPS------DTDYRVFRDYGGLPGLDIAFYKNRY--------VYHTKYDTA 255


                 ....*
gi 767967355 504 DYVDK 508
Cdd:cd03875  256 DHISR 260
M28_Pgcp_like cd03883
M28 Zn-Peptidase Plasma glutamate carboxypeptidase; Peptidase M28 family; Plasma glutamate ...
 124-508 2.71e-14

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.


Pssm-ID: 349879 [Multi-domain]  Cd Length: 425  Bit Score: 75.42  E-value: 2.71e-14
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 124 EDFKELQTQGIKLEGTIAL-----TRYG--GVGRGAKAVNAAKHGVAGVLVYTdpadINdglsspdetfPNSWYLPPSGV 196
Cdd:cd03883  112 FSFEELQAKADEVKGKIVVynqpfKGYGetVKYRGQGAVEAAKYGAVAVLIRS----IT----------PFSIYSPHTGI 177

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 197 ERgsyYEyfgdpltpylpavpssfrvdlanvSGFPPIPTQPIGFQDArDLLCNLngtlapatwqgalgchYRLGPGFRPD 276
Cdd:cd03883  178 MR---YQ------------------------DGVTKIPAAAITVEDA-EMLSRM----------------AARGQKIVIE 213

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 277 GDFPADSQVNVsvynrlelrNSSNVLGIIRGAVEPDRYVLYGNHRDSW--VHGAVDPSSGTAVLLELSRVLGTLLKkgtw 354
Cdd:cd03883  214 LKMEAKTYPDA---------TSRNVIAEITGSKYPDEVVLVGGHLDSWdvGTGAMDDGGGVAISWEALKLIKDLGL---- 280

                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 355 RPRRSIVFASWGAEEFGLIGSTEFTEEFFNKLQERTVAyINVDISVFanatlrvqgTPPVQSvvFSATKEIRspgpgdlS 434
Cdd:cd03883  281 KPKRTIRVVLWTGEEQGLVGAKAYAEAHKDELENHVFA-MESDIGTF---------TPYGLQ--FTGSDTAR-------A 341

                        330       340       350       360       370       380       390
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767967355 435 IYDNWIRYFNRSSPVYGLVPSlgslGAGSDYAPFVHfLGISSMdiAYTYDRSKtsariYPTY-HTAFDTFDYVDK 508
Cdd:cd03883  342 IVKEVMKLLSPLGITQVLPKA----GVGPDISFLKA-AGVPGA--SLIQDNSD-----YFDYhHTAGDTMDVMDP 404
M28_like_PA_PDZ_associated cd05663
M28 Zn-peptidase containing a protease-associated (PA) domain insert and associated with a PDZ ...
 300-411 2.62e-12

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


Pssm-ID: 349913 [Multi-domain]  Cd Length: 266  Bit Score: 67.48  E-value: 2.62e-12
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 300 NVLGII-RGAVEPDRYVLYGNHRD---------------SWVH-GAVDPSSGTAVLLELSRVLGTLLKKGTwrPRRSIVF 362
Cdd:cd05663   57 NVIGVLpGKGDVADETVVVGAHYDhlgyggegslargdeSLIHnGADDNASGVAAMLELAAKLVDSDTSLA--LSRNLVF 134

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 767967355 363 ASWGAEEFGLIGSTEFTEEfFNKLQERTVAYINVD-ISVFANATLRVQGT 411
Cdd:cd05663  135 IAFSGEELGLLGSKHFVKN-PPFPIKNTVYMINMDmVGRLRDNKLIVQGT 183
M28_SGAP_like cd03876
M28 Zn-peptidase Streptomyces griseus aminopeptidase and similar proteins; Peptidase family ...
 296-508 5.13e-12

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.


Pssm-ID: 349873 [Multi-domain]  Cd Length: 289  Bit Score: 66.94  E-value: 5.13e-12
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 296 RNSSNVLGIIRGAvEPDRYVLYGNHRDSwVH---GAVDPSSGTAVLLELSRVLGTllkkgtWRPRRSIVFASWGAEEFGL 372
Cdd:cd03876   61 RTTYNVIAETKGG-DPNNVVMLGAHLDS-VSagpGINDNGSGSAALLEVALALAK------FKVKNAVRFAWWTAEEFGL 132

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 373 IGSTEFTEEFFNKLQERTVAYINVDI--SV-FANATLRVQGTPPVqsvvfsatkeiRSPGPGDLSIYDNWIRYFNRSSpv 449
Cdd:cd03876  133 LGSKFYVNNLSSEERSKIRLYLNFDMiaSPnYGYFIYDGDGSAFN-----------LTGPPGSAEIERLFEAYFTSLG-- 199

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967355 450 yglVPSLGSLGAG-SDYAPFVHfLGISSMDIAYTYDRSKTSA----------RIY-PTYHTAFDTFDYVDK 508
Cdd:cd03876  200 ---LPSTPTEFDGrSDYAPFIE-AGIPAGGLFTGAEGIKTEEqaalwggtagVAYdPCYHQACDTIDNINR 266
M28_PSMA_like cd08022
M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific ...
 1-73 1.17e-11

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.


Pssm-ID: 349942 [Multi-domain]  Cd Length: 287  Bit Score: 66.10  E-value: 1.17e-11
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767967355   1 MGQLDAHRIRENLRELSREPHLASSPRDEDLVQLLLQRWKDPesGLDSAEASTYEVLL-----SFPSQEQPNVVDIVG 73
Cdd:cd08022    5 LDEPDAENIREWLRYYTSGPHLAGTEGNLELAQWTEDKWREF--GLDDVELEEYDVPIwnvigTIRGSEEPDEYIILG 80
M28_like cd05662
M28 Zn-Peptidases; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized ...
 292-510 3.37e-11

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.


Pssm-ID: 349912 [Multi-domain]  Cd Length: 268  Bit Score: 64.41  E-value: 3.37e-11
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 292 RLELRNSSNVLGIIRGAVEPDRYVLYGNHRD-------SWVHGAVDPSSGTAVLLELSRVLGTllkkgtWRPRRSIVFAS 364
Cdd:cd05662   56 RFSTRQGVNVLAVIKGSEPPTKWRVVSAHYDhlgirggKIYNGADDNASGVAALLALAEYFKK------HPPKHNVIFAA 129

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 365 WGAEEFGLIGSTEFTEEFFNKLQERTVAyINVD-ISVFANATLRVQG-------TPPVQSVVFSATKEIRSPGPGDLSIY 436
Cdd:cd05662  130 TDAEEPGLRGSYAFVEALKVPRAQIELN-INLDmISRPERNELYVEGasqfpqlTSILENVKGTCIKALHPKDTDGSIGS 208

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767967355 437 DNWIRyfnrsspvyglvpslgslgaGSDYAPFvHFLGISsmdiaYTYdrskTSARIYPTYHTAFDTFDYVD-KFL 510
Cdd:cd05662  209 IDWTR--------------------ASDHYPF-HKAKIP-----WLY----FGVEDHPDYHKPTDDFETIDqEFF 253
PA pfam02225
PA domain; The PA (Protease associated) domain is found as an insert domain in diverse ...
 112-200 1.42e-10

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.


Pssm-ID: 460499 [Multi-domain]  Cd Length: 91  Bit Score: 58.29  E-value: 1.42e-10
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  112 QGLLVYANRGAEEDFkelQTQGIKLEGTIALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPAD-INDGLSSPDETFPNSWY 190
Cdd:pfam02225   1 TGPLVLAPGCYAGDG---IPADFDVKGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGlGGPPGAGGNELYPDGIY 77

                          90
                  ....*....|
gi 767967355  191 LPPSGVERGS 200
Cdd:pfam02225  78 IPAVGVSRAD 87
M28_like_PA cd05661
M28 Zn-peptidase containing a PA domain insert; Peptidase family M28 (also called ...
 298-508 3.91e-10

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.


Pssm-ID: 349911 [Multi-domain]  Cd Length: 262  Bit Score: 61.05  E-value: 3.91e-10
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 298 SSNVLGIIR--GAVEPDRYVLYGNHRDSWVH--GAVDPSSGTAVLLELSRVLGTLlkkgtwRPRRSIVFASWGAEEFGLI 373
Cdd:cd05661   60 SHNVIATKKpdNNKNNNDIIIVTSHYDSVVKapGANDNASGTAVTLELARVFKKV------KTDKELRFIAFGAEENGLL 133

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 374 GSTEFTEEFFNKLQERTVAYINVDIsvfanatlrVQGTPPVQSVVFSATKEirspGPGDLsIYDNWIRYFNRSSPVYGLV 453
Cdd:cd05661  134 GSKYYVASLSEDEIKRTIGVFNLDM---------VGTSDAKAGDLYAYTID----GKPNL-VTDSGAAASKRLSGVLPLV 199

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 767967355 454 pslgsLGAGSDYAPFvHFLGISSMDIAYTydrSKTSARIYPTYHTAFDTFDYVDK 508
Cdd:cd05661  200 -----QQGSSDHVPF-HEAGIPAALFIHM---DPETEPVEPWYHTPNDTVENISK 245
M28_like cd05642
M28 Zn-peptidase-like; uncharacterized subfamily; Peptidase family M28 (also called ...
 297-426 4.69e-10

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


Pssm-ID: 349894 [Multi-domain]  Cd Length: 347  Bit Score: 61.74  E-value: 4.69e-10
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 297 NSSNVLGIIRGAVEPDRYVLYGNHRDSWVH----------GAVDPSSGTAVLLELSRVLgtllkkGTWRPRRSIVFASWG 366
Cdd:cd05642   87 NISNVVATLKGSEDPDRVYVVSGHYDSRVSdvmdyesdapGANDDASGVAVSMELARIF------AKHRPKATIVFTAVA 160

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 367 AEEFGLIGSTeFTEEFFNKLQERTVAYINVDI--------SVFANATLRV--QGTPPVQSvvfSATKEIR 426
Cdd:cd05642  161 GEEQGLYGST-FLAQTYRNNSVNVEGMLNNDIvgsstgddGTKDPHTIRLfaQGTPAVES---SEQAESR 226
PA_hNAALADL2_like cd02131
PA_hNAALADL2_like: Protease-associated domain containing proteins like human N-acetylated ...
 97-247 2.18e-09

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.


Pssm-ID: 239046  Cd Length: 153  Bit Score: 56.48  E-value: 2.18e-09
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  97 DVVQPYAAYAPSGTPQGLLVYANRGAEEDFKELQTQgIKLEGTIALTRYGGVGRGAKAVNAAKHGVAGVLVYTDPADIND 176
Cdd:cd02131    1 DLLYSYAAYSAKGTLQAEVVDVQYGSVEDLRRIRDN-MNVTNQIALLKLGQAPLLYKLSLLEEAGFGGVLLYVDPCDLPK 79

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767967355 177 GLSSPDETFPNSwyLPPSgvergsyyeyfGDPLTPYLPAVPSSFRvdlANVSGFPPIPTQPIGFQDARDLL 247
Cdd:cd02131   80 TRHTWHQAFMVS--LNPG-----------GDPSTPGYPSADQSCR---QCRGNLTSLLVQPISAYLAKKLL 134
PA cd00538
PA: Protease-associated (PA) domain. The PA domain is an insert domain in a diverse fraction ...
 90-196 8.61e-09

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.


Pssm-ID: 238300 [Multi-domain]  Cd Length: 126  Bit Score: 54.06  E-value: 8.61e-09
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355  90 TGEQGGPDVVQPYAAYAPSGTPQGL----LVYANRGAEEDFkelqtqGIKLEGTIALTRYGGVGRGAKAVNAAKHGVAGV 165
Cdd:cd00538    1 DVILATTGYAGSALLFNPPSSPVGVvagpLVGCGYGTTDDS------GADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAV 74

                         90       100       110
                 ....*....|....*....|....*....|.
gi 767967355 166 LVYTDPADINDGLSSPDETFPNSWyLPPSGV 196
Cdd:cd00538   75 IIYNNGDDPGPQMGSVGLESTDPS-IPTVGI 104
M28_like cd05643
M28 Zn-peptidase-like; Peptidase family M28 (also called aminopeptidase Y family), ...
 294-508 3.08e-07

M28 Zn-peptidase-like; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They typically 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 protein subfamily conserves some of the metal-coordinating residues of the typically co-catalytic M28 family which might suggest binding of a single metal ion.


Pssm-ID: 349895 [Multi-domain]  Cd Length: 290  Bit Score: 52.41  E-value: 3.08e-07
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 294 ELRNSSNVLGIIRGAvEPDRYVLYGNHRDSWVHGAVDPSSGTAVLLELSRVLGTLLKKgtwRPRRSIVFAsWGAEEFGli 373
Cdd:cd05643   66 ELNETLPILYAIIGK-ETPPEIAFVAHLCHPKPGANDNASGSALLLEVARVLAKLILN---RPKRGICFL-WVPEYTG-- 138

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 374 gstefTEEFFNKLQER---TVAYINVDIsVFANATlRVQGTppvqsVVFSATKeIRSPGPGDLSIYDNwIRYFNRSSPV- 449
Cdd:cd05643  139 -----TAAYFAQHPDRlkkIIAVINLDM-VGEDQT-KTGST-----LMLVPTP-LSFPSYLNEELAQK-LSNFTGSSLPa 204

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 767967355 450 --YGLVPSLGslgaGSDYAPFVhFLGI-SSMDIAYTyDRSktsariyptYHTAFDTFDYVDK 508
Cdd:cd05643  205 vrYGKEPYEG----GSDHDVFS-DPGIpAVMFNTWP-DRY---------YHTSDDTPDKLDP 251
PA_C5a_like cd02133
PA_C5a_like: Protease-associated domain containing proteins like Streptococcus pyogenes C5a ...
 115-168 4.02e-07

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.


Pssm-ID: 239048 [Multi-domain]  Cd Length: 143  Bit Score: 49.98  E-value: 4.02e-07
                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 767967355 115 LVYANRGAEEDFKelqtqGIKLEGTIALTRYGGVGRGAKAVNAAKHGVAGVLVY 168
Cdd:cd02133   30 LVDAGLGTPEDFE-----GKDVKGKIALIQRGEITFVEKIANAKAAGAVGVIIY 78
M28_AAP cd03879
M28 Zn-peptidase Aeromonas (Vibrio) proteolytica aminopeptidase; Peptidase family M28; ...
 299-375 5.52e-07

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.


Pssm-ID: 349875 [Multi-domain]  Cd Length: 286  Bit Score: 51.86  E-value: 5.52e-07
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 299 SNVLGIIRGAVEPDRYVLYGNHRDSWVH---------GAVDPSSGTAVLLELSRVLgtlLKKGtWRPRRSIVFASWGAEE 369
Cdd:cd03879   75 PSIIATIPGSEKSDEIVVIGAHQDSINGsnpsngrapGADDDGSGTVTILEALRVL---LESG-FQPKNTIEFHWYAAEE 150


                 ....*.
gi 767967355 370 FGLIGS 375
Cdd:cd03879  151 GGLLGS 156
M28_like cd05640
M28 Zn-peptidase; uncharacterized subfamily; Peptidase family M28 (also called aminopeptidase ...
 300-381 4.13e-06

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


Pssm-ID: 349893 [Multi-domain]  Cd Length: 281  Bit Score: 48.98  E-value: 4.13e-06
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 300 NVLGIIRGAVEPDRYVLYGNHRDSW--VHGAVDPSSGTAVLLELSRVLGTLlkkgtwRPRRSIVFASWGAEEF-----GL 372
Cdd:cd05640   54 NLIADLPGSYSQDKLILIGAHYDTVpgSPGADDNASGVAALLELARLLATL------DPNHTLRFVAFDLEEYpffarGL 127


                 ....*....
gi 767967355 373 IGSTEFTEE 381
Cdd:cd05640  128 MGSHAYAED 136
PA_ScAPY_like cd02130
PA_ScAPY_like: Protease-associated domain containing proteins like Saccharomyces cerevisiae ...
 104-185 4.26e-06

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.


Pssm-ID: 239045 [Multi-domain]  Cd Length: 122  Bit Score: 46.48  E-value: 4.26e-06
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767967355 104 AYAPSGTPQGLLVYA-NRG-AEEDFKElqtqgiKLEGTIALTRYGGVGRGAKAVNAAKHGVAGVLVYT--DPADINDGLS 179
Cdd:cd02130   15 TYSPAGEVTGPLVVVpNLGcDAADYPA------SVAGNIALIERGECPFGDKSALAGAAGAAAAIIYNnvPAGGLSGTLG 88


                 ....*.
gi 767967355 180 SPDETF 185
Cdd:cd02130   89 EPSGPY 94
M28_Nicastrin cd03881
M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, ...
 327-378 5.90e-05

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


Pssm-ID: 349877 [Multi-domain]  Cd Length: 519  Bit Score: 46.26  E-value: 5.90e-05
                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 767967355 327 GAVDPSSGTAVLLELSRVLGTLLKKGTWRprRSIVFASWGAEEFGLIGSTEF 378
Cdd:cd03881  231 GADSSLSGFVALLAAAEALKKVDGKGSLK--RNVVFAFFNGESWGYIGSSRF 280
PA_2 cd04819
PA_2: Protease-associated (PA) domain subgroup 2. A subgroup of PA-domain containing proteins. ...
 105-177 1.71e-04

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


Pssm-ID: 240123 [Multi-domain]  Cd Length: 127  Bit Score: 42.00  E-value: 1.71e-04
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767967355 105 YAPSGTPQGLLVYANRGAEEDFkelqtQGIKLEGTIALTRYGG--VGRGAKAVNAAKHGVAGVLVYtdpaDINDG 177
Cdd:cd04819   17 RSPSGEAKGEPVDAGYGLPKDF-----DGLDLEGKIAVVKRDDpdVDRKEKYAKAVAAGAAAFVVV----NTVPG 82
M28_TfR cd09848
M28 Zn-peptidase Transferrin Receptor family; Peptidase M28 family; Transferrin Receptor (TfR) ...
 4-41 6.98e-03

M28 Zn-peptidase Transferrin Receptor family; Peptidase M28 family; Transferrin Receptor (TfR) subfamily. TfRs 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). While related in sequence to peptidase M28 glutamate carboxypeptidase II (also called prostate-specific membrane antigen or PSMA), TfR lacks the metal ion coordination centers and protease activity of that group.


Pssm-ID: 349946 [Multi-domain]  Cd Length: 285  Bit Score: 38.89  E-value: 6.98e-03
                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 767967355   4 LDAHRIRENLRELSREPHLASSPRDEDLVQLLLQRWKD 41
Cdd:cd09848    5 LSEKDFEQTLRDLSSISHEAGSSGDENLANYIMNEFKN 42
 
Blast search parameters
Data Source: Precalculated data, version = cdd.v.3.21
Preset Options:Database: CDSEARCH/cdd   Low complexity filter: no  Composition Based Adjustment: yes   E-value threshold: 0.01

References:

  • Wang J et al. (2023), "The conserved domain database in 2023", Nucleic Acids Res.51(D)384-8.
  • Lu S et al. (2020), "The conserved domain database in 2020", Nucleic Acids Res.48(D)265-8.
  • Marchler-Bauer A et al. (2017), "CDD/SPARCLE: functional classification of proteins via subfamily domain architectures.", Nucleic Acids Res.45(D)200-3.
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