NCBI Home Page NCBI Site Search page NCBI Guide that lists and describes the NCBI resources
Conserved domains on  [gi|6322586|ref|NP_012660|]
View 

putative zinc metalloprotease [Saccharomyces cerevisiae S288C]

Protein Classification

M28 family metallopeptidase( domain architecture ID 10114702)

M28 family metallopeptidase is a zinc-dependent peptidase that may be an aminopeptidase or a carboxypeptidase with co-catalytic zinc ions; contains a protease-associated (PA) domain insert which may participate in substrate binding and/or promote conformational changes; 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

 Zoom to residue level

show extra options »

Show site features     Horizontal zoom: ×

List of domain hits

 Name Accession Description Interval E-value
M28_PMSA_TfR_like cd03874
M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor ...
 419-649 2.55e-92

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: 291.12  E-value: 2.55e-92
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  419 YNIKEMSSVEVSIPGI-FTEGEIIIGAHRDSlASSSAGDANSGSAILLEIARGMSKLLKH-GWKPLRPIKLISWDGERSG 496
Cdd:cd03874  52 EEYSPITNVVGKIEGIeQPDRAIIIGAHRDS-WGYGAGYPNSGTAVLLEIARLFQQLKKKfGWKPLRTIYFISWDGSEFG 130

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  497 LLGSTDYAEAHAAILRRRALVYLNLDNAISG-TNFHCKANPLLQDVIYEAAKLTEFNGHEDWslfdhWKYTSNATISLLD 575
Cdd:cd03874 131 LAGSTELGEDRKASLKDEVYAYINIDQLVIGnSELDVDAHPLLQSLFRKASKKVKFPGNEDW-----WKHSPNAKVSNLH 205

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 6322586  576 GLSSYTSFQYHLGVPAAHFQFNANDtsGAVYHSNSVFDSPTWLEKFTNSDYKLHNTMAMFVGLTTLMLSENELA 649
Cdd:cd03874 206 QYGDWTPFLNHLGIPVAVFSFKNDR--NASYPINSSYDTFEWLEKFLDPDFELHSTLAEFVGLLVLSLAEDPLL 277
PA_GCPII_like cd02121
PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II ...
 187-413 4.09e-90

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: 283.03  E-value: 4.09e-90
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  187 PWIGEPVDTNVAPLENgkvvyeaSMIEDRVKGDPAShaRKRQKGFHQYSKNGSVTARYVFCNYGSISDYKLLLKKNIDIE 266
Cdd:cd02121   1 PVKRSLILTKPDGATG-------KLIEDTVLEEPPS--PDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVK 71

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  267 DKIHIVRSGKILPGLKVKNAELYGASSVIIYTDPFDDGKVTEENGfLHYPYGPARNPSYIRRDSVNYFSDTPGDPTTPGY 346
Cdd:cd02121  72 GKIVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENG-KTYPDGPARPPSGVQRGSVLFMSIGPGDPLTPGY 150

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 6322586  347 PSKDSDTEHM-SPVGRVPRIPSVPMSARDVQPILERLNGRG----FQIGPGSNIKDFgsFTGPSSSIDKVHL 413
Cdd:cd02121 151 PSKPGAERRDkEESKGLPKIPSLPISYRDAQPLLKALGGPGapsdWQGGLPVTYRLG--FGGPSPGKVRVNL 220
TFR_dimer pfam04253
Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the ...
 725-799 4.57e-08

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: 51.82  E-value: 4.57e-08
                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 6322586    725 KKIKSYIKLQRSNSKSKQIDQLFITHRGLKDREWMKYSLLAPSKFEGSVGEVLPGLHEGLADIDRNEVIQWLTIL 799
Cdd:pfam04253  30 IKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGATFPGIRDAIEAGDWELAQKQISIV 104
Zinc_peptidase_like super family cl14876
Zinc peptidases M18, M20, M28, and M42; Zinc peptidases play vital roles in metabolic and ...
 135-187 4.04e-06

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 cd03874:

Pssm-ID: 472712 [Multi-domain]  Cd Length: 278  Bit Score: 49.22  E-value: 4.04e-06
                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 6322586  135 YLNSLQQENRAKEHVYKYA--GYMSNGASDSSTFKYTLDEFLDMG-YKPKVEKYYP 187
Cdd:cd03874   1 YARKLVDLAKIKEDLEYLSsmPHMAGTKGDAALAKYIENSFKNNGlFEVELEEYSP 56
 
Name Accession Description Interval E-value
M28_PMSA_TfR_like cd03874
M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor ...
 419-649 2.55e-92

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: 291.12  E-value: 2.55e-92
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  419 YNIKEMSSVEVSIPGI-FTEGEIIIGAHRDSlASSSAGDANSGSAILLEIARGMSKLLKH-GWKPLRPIKLISWDGERSG 496
Cdd:cd03874  52 EEYSPITNVVGKIEGIeQPDRAIIIGAHRDS-WGYGAGYPNSGTAVLLEIARLFQQLKKKfGWKPLRTIYFISWDGSEFG 130

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  497 LLGSTDYAEAHAAILRRRALVYLNLDNAISG-TNFHCKANPLLQDVIYEAAKLTEFNGHEDWslfdhWKYTSNATISLLD 575
Cdd:cd03874 131 LAGSTELGEDRKASLKDEVYAYINIDQLVIGnSELDVDAHPLLQSLFRKASKKVKFPGNEDW-----WKHSPNAKVSNLH 205

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 6322586  576 GLSSYTSFQYHLGVPAAHFQFNANDtsGAVYHSNSVFDSPTWLEKFTNSDYKLHNTMAMFVGLTTLMLSENELA 649
Cdd:cd03874 206 QYGDWTPFLNHLGIPVAVFSFKNDR--NASYPINSSYDTFEWLEKFLDPDFELHSTLAEFVGLLVLSLAEDPLL 277
PA_GCPII_like cd02121
PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II ...
 187-413 4.09e-90

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: 283.03  E-value: 4.09e-90
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  187 PWIGEPVDTNVAPLENgkvvyeaSMIEDRVKGDPAShaRKRQKGFHQYSKNGSVTARYVFCNYGSISDYKLLLKKNIDIE 266
Cdd:cd02121   1 PVKRSLILTKPDGATG-------KLIEDTVLEEPPS--PDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVK 71

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  267 DKIHIVRSGKILPGLKVKNAELYGASSVIIYTDPFDDGKVTEENGfLHYPYGPARNPSYIRRDSVNYFSDTPGDPTTPGY 346
Cdd:cd02121  72 GKIVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENG-KTYPDGPARPPSGVQRGSVLFMSIGPGDPLTPGY 150

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 6322586  347 PSKDSDTEHM-SPVGRVPRIPSVPMSARDVQPILERLNGRG----FQIGPGSNIKDFgsFTGPSSSIDKVHL 413
Cdd:cd02121 151 PSKPGAERRDkEESKGLPKIPSLPISYRDAQPLLKALGGPGapsdWQGGLPVTYRLG--FGGPSPGKVRVNL 220
Iap COG2234
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein ...
 427-610 2.05e-22

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: 97.51  E-value: 2.05e-22
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  427 VEVSIPGI-FTEGEIIIGAHRDSLASSSAG--DANSGSAILLEIARGMSKllkHGWKPLRPIKLISWDGERSGLLGSTDY 503
Cdd:COG2234  49 VIAEIPGTdPPDEVVVLGAHYDSVGSIGPGadDNASGVAALLELARALAA---LGPKPKRTIRFVAFGAEEQGLLGSRYY 125

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  504 AEAHAAILrRRALVYLNLDNAISGTNFH------CKANPLLQDVIYEAAKltefnghedwSLFDHWKYTSNATISLLDGl 577
Cdd:COG2234 126 AENLKAPL-EKIVAVLNLDMIGRGGPRNylyvdgDGGSPELADLLEAAAK----------AYLPGLGVDPPEETGGYGR- 193

                       170       180       190
                ....*....|....*....|....*....|...
gi 6322586  578 SSYTSFqYHLGVPAAHFqFNANDTSGAVYHSNS 610
Cdd:COG2234 194 SDHAPF-AKAGIPALFL-FTGAEDYHPDYHTPS 224
Peptidase_M28 pfam04389
Peptidase family M28;
429-608 1.55e-19

Peptidase family M28;


Pssm-ID: 461288 [Multi-domain]  Cd Length: 192  Bit Score: 87.34  E-value: 1.55e-19
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586    429 VSIPGIFTEGEIIIGAHRDSLASSS-AGDANSGSAILLEIARGmsklLKHGWKPLRPIKLISWDGERSGLLGSTDYAEAH 507
Cdd:pfam04389   4 AKLPGKAPDEVVLLSAHYDSVGTGPgADDNASGVAALLELARV----LAAGQRPKRSVRFLFFDAEEAGLLGSHHFAKSH 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586    508 AAILRRRAlvYLNLDNAISGtnfhckaNPLLQDVIYEAakltefNGHEDWSLFDHWKYTSNATI-------SLLDGLSSY 580
Cdd:pfam04389  80 PPLKKIRA--VINLDMIGSG-------GPALLFQSGPK------GSSLLEKYLKAAAKPYGVTLaedpfqeRGGPGRSDH 144

                         170       180
                  ....*....|....*....|....*...
gi 6322586    581 TSFQyHLGVPAAHFQFNANdtsGAVYHS 608
Cdd:pfam04389 145 APFI-KAGIPGLDLAFTDF---GYRYHT 168
TFR_dimer pfam04253
Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the ...
 725-799 4.57e-08

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: 51.82  E-value: 4.57e-08
                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 6322586    725 KKIKSYIKLQRSNSKSKQIDQLFITHRGLKDREWMKYSLLAPSKFEGSVGEVLPGLHEGLADIDRNEVIQWLTIL 799
Cdd:pfam04253  30 IKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGATFPGIRDAIEAGDWELAQKQISIV 104
M28_PMSA_TfR_like cd03874
M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor ...
 135-187 4.04e-06

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: 49.22  E-value: 4.04e-06
                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 6322586  135 YLNSLQQENRAKEHVYKYA--GYMSNGASDSSTFKYTLDEFLDMG-YKPKVEKYYP 187
Cdd:cd03874   1 YARKLVDLAKIKEDLEYLSsmPHMAGTKGDAALAKYIENSFKNNGlFEVELEEYSP 56
PA pfam02225
PA domain; The PA (Protease associated) domain is found as an insert domain in diverse ...
 240-319 6.90e-06

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: 45.20  E-value: 6.90e-06
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586    240 VTARYVFCNYGSISDYklllkkniDIEDKIHIVRSGKILPGLKVKNAELYGASSVIIYTDPFDDGKVTEENGFLHYPYGP 319
Cdd:pfam02225   5 VLAPGCYAGDGIPADF--------DVKGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPPGAGGNELYPDGI 76
PRK10199 PRK10199
alkaline phosphatase isozyme conversion aminopeptidase; Provisional
 350-527 7.37e-06

alkaline phosphatase isozyme conversion aminopeptidase; Provisional


Pssm-ID: 182299 [Multi-domain]  Cd Length: 346  Bit Score: 48.97  E-value: 7.37e-06
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586   350 DSDTEHMSPV--GRVPRIPSVPMSArdvqpilERLNGRGFQIGPGSNIKDFGSFTGPSSSIDKVHLHNeLTynikeMSSV 427
Cdd:PRK10199  34 NTQARHIATFfpGRMTGSPAEMLSA-------DYLRQQFQQMGYQSDIRTFNSRYIYTARDNRKNWHN-VT-----GSTV 100

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586   428 ----EVSIPGiftegEIIIGAHRDSLASSSAGDAN---------------SGSAILLEIARGMSKllkhgwKPLR-PIKL 487
Cdd:PRK10199 101 iaahEGKAPQ-----QIIIMAHLDTYAPQSDADVDanlggltlqgmddnaAGLGVMLELAERLKN------VPTEyGIRF 169

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 6322586   488 ISWDGERSGLLGSTDYAEAHAAILRRRALVYLNLDNAISG 527
Cdd:PRK10199 170 VATSGEEEGKLGAENLLKRMSDTEKKNTLLVINLDNLIVG 209
 
Name Accession Description Interval E-value
M28_PMSA_TfR_like cd03874
M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor ...
 419-649 2.55e-92

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: 291.12  E-value: 2.55e-92
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  419 YNIKEMSSVEVSIPGI-FTEGEIIIGAHRDSlASSSAGDANSGSAILLEIARGMSKLLKH-GWKPLRPIKLISWDGERSG 496
Cdd:cd03874  52 EEYSPITNVVGKIEGIeQPDRAIIIGAHRDS-WGYGAGYPNSGTAVLLEIARLFQQLKKKfGWKPLRTIYFISWDGSEFG 130

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  497 LLGSTDYAEAHAAILRRRALVYLNLDNAISG-TNFHCKANPLLQDVIYEAAKLTEFNGHEDWslfdhWKYTSNATISLLD 575
Cdd:cd03874 131 LAGSTELGEDRKASLKDEVYAYINIDQLVIGnSELDVDAHPLLQSLFRKASKKVKFPGNEDW-----WKHSPNAKVSNLH 205

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 6322586  576 GLSSYTSFQYHLGVPAAHFQFNANDtsGAVYHSNSVFDSPTWLEKFTNSDYKLHNTMAMFVGLTTLMLSENELA 649
Cdd:cd03874 206 QYGDWTPFLNHLGIPVAVFSFKNDR--NASYPINSSYDTFEWLEKFLDPDFELHSTLAEFVGLLVLSLAEDPLL 277
PA_GCPII_like cd02121
PA_GCPII_like: Protease-associated domain containing protein, glutamate carboxypeptidase II ...
 187-413 4.09e-90

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: 283.03  E-value: 4.09e-90
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  187 PWIGEPVDTNVAPLENgkvvyeaSMIEDRVKGDPAShaRKRQKGFHQYSKNGSVTARYVFCNYGSISDYKLLLKKNIDIE 266
Cdd:cd02121   1 PVKRSLILTKPDGATG-------KLIEDTVLEEPPS--PDVVPPFHAYSASGNVTAELVYANYGSPEDFEYLEDLGIDVK 71

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  267 DKIHIVRSGKILPGLKVKNAELYGASSVIIYTDPFDDGKVTEENGfLHYPYGPARNPSYIRRDSVNYFSDTPGDPTTPGY 346
Cdd:cd02121  72 GKIVIARYGGIFRGLKVKNAQLAGAVGVIIYSDPADDGYITGENG-KTYPDGPARPPSGVQRGSVLFMSIGPGDPLTPGY 150

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 6322586  347 PSKDSDTEHM-SPVGRVPRIPSVPMSARDVQPILERLNGRG----FQIGPGSNIKDFgsFTGPSSSIDKVHL 413
Cdd:cd02121 151 PSKPGAERRDkEESKGLPKIPSLPISYRDAQPLLKALGGPGapsdWQGGLPVTYRLG--FGGPSPGKVRVNL 220
M28_PSMA_like cd08022
M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific ...
 431-648 2.37e-62

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: 211.32  E-value: 2.37e-62
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  431 IPGIFTEGE-IIIGAHRDSLaSSSAGDANSGSAILLEIARGMSKLLKHGWKPLRPIKLISWDGERSGLLGSTDYAEAHAA 509
Cdd:cd08022  67 IRGSEEPDEyIILGNHRDAW-VFGAGDPNSGTAVLLEVARALGTLLKKGWRPRRTIIFASWDAEEYGLIGSTEWVEENAD 145

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  510 ILRRRALVYLNLDNAISGTNFHCKANPLLQDVIYEAAKLTEF-NGHEDWSLFDHWKYTSNATISLLDGLSSYTSFQYHLG 588
Cdd:cd08022 146 WLQERAVAYLNVDVAVSGSTLRAAGSPLLQNLLREAAKEVQDpDEGATLKYLPSWWDDTGGEIGNLGSGSDYTPFLDHLG 225

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  589 VPAAHFQFnANDTSGAVYHSNSVFDSPTWLEKFTNSDYKLHNTMAMFVGLTTLMLSENEL 648
Cdd:cd08022 226 IASIDFGF-SGGPTDPYPHYHSNYDSFEWMEKFGDPGFKYHVAIAQVWGLLALRLADDPI 284
M28_TfR cd09848
M28 Zn-peptidase Transferrin Receptor family; Peptidase M28 family; Transferrin Receptor (TfR) ...
 440-652 3.84e-29

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: 117.86  E-value: 3.84e-29
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  440 IIIGAHRDSLASSSAgDANSGSAILLEIARGMSKLLKH-GWKPLRPIKLISWDGERSGLLGSTDYAEAHAAILRRRALVY 518
Cdd:cd09848  73 VVIGAQRDAWGPGAA-KSGVGTALLLELARTFSDMVKNdGFKPRRSIVFASWSAGDFGSVGATEWLEGYLSSLHLKAFTY 151

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  519 LNLDNAISGT-NFHCKANPLLQDVIYEAAKLTEFNGHEDWSLFDHWKYTSNATISLLDGLSSYTSFQYHLGVPAAHFQFN 597
Cdd:cd09848 152 ISLDGAVLGDdSFKASASPLLYTLIESTMKQVKSPVHSGQSYYETRSSWWASIVEPLGLDSAAYPFLAFSGIPSVSFHFT 231

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 6322586  598 ANDTSGAVYHSNsvFDSPTWLEKFTNSDY-KLHNTMAMFVGLTTLMLSENELARFN 652
Cdd:cd09848 232 EDDEDYPFLGTK--EDTKENLDKFTNGELwEVAAAAAEVAGQMALRLVHDHLLPLD 285
Iap COG2234
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein ...
 427-610 2.05e-22

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: 97.51  E-value: 2.05e-22
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  427 VEVSIPGI-FTEGEIIIGAHRDSLASSSAG--DANSGSAILLEIARGMSKllkHGWKPLRPIKLISWDGERSGLLGSTDY 503
Cdd:COG2234  49 VIAEIPGTdPPDEVVVLGAHYDSVGSIGPGadDNASGVAALLELARALAA---LGPKPKRTIRFVAFGAEEQGLLGSRYY 125

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  504 AEAHAAILrRRALVYLNLDNAISGTNFH------CKANPLLQDVIYEAAKltefnghedwSLFDHWKYTSNATISLLDGl 577
Cdd:COG2234 126 AENLKAPL-EKIVAVLNLDMIGRGGPRNylyvdgDGGSPELADLLEAAAK----------AYLPGLGVDPPEETGGYGR- 193

                       170       180       190
                ....*....|....*....|....*....|...
gi 6322586  578 SSYTSFqYHLGVPAAHFqFNANDTSGAVYHSNS 610
Cdd:COG2234 194 SDHAPF-AKAGIPALFL-FTGAEDYHPDYHTPS 224
Peptidase_M28 pfam04389
Peptidase family M28;
429-608 1.55e-19

Peptidase family M28;


Pssm-ID: 461288 [Multi-domain]  Cd Length: 192  Bit Score: 87.34  E-value: 1.55e-19
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586    429 VSIPGIFTEGEIIIGAHRDSLASSS-AGDANSGSAILLEIARGmsklLKHGWKPLRPIKLISWDGERSGLLGSTDYAEAH 507
Cdd:pfam04389   4 AKLPGKAPDEVVLLSAHYDSVGTGPgADDNASGVAALLELARV----LAAGQRPKRSVRFLFFDAEEAGLLGSHHFAKSH 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586    508 AAILRRRAlvYLNLDNAISGtnfhckaNPLLQDVIYEAakltefNGHEDWSLFDHWKYTSNATI-------SLLDGLSSY 580
Cdd:pfam04389  80 PPLKKIRA--VINLDMIGSG-------GPALLFQSGPK------GSSLLEKYLKAAAKPYGVTLaedpfqeRGGPGRSDH 144

                         170       180
                  ....*....|....*....|....*...
gi 6322586    581 TSFQyHLGVPAAHFQFNANdtsGAVYHS 608
Cdd:pfam04389 145 APFI-KAGIPGLDLAFTDF---GYRYHT 168
PA_TfR cd02128
PA_TfR: Protease-associated domain containing proteins like transferrin receptor (TfR). This ...
 204-385 1.07e-18

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: 84.76  E-value: 1.07e-18
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  204 KVVYEASMIEDRVKGDPasharkrqKGFHQYSKNGSVTARYVFCNYGSISDYKLLLKKNIDIEDKIHIVRSGKILPGLKV 283
Cdd:cd02128   1 SVIIGDAGRLNELVENP--------GGYVAYSAAGTVTGKLVYANYGRKKDFEDLQSVGVSVNGSVVLVRAGKISFAEKV 72

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  284 KNAELYGASSVIIYTDPFDDGKVTEENGflhyPYGPARNPSyirrdsvnyfsdtpGDPTTPGYPSKDsdteH--MSPVGR 361
Cdd:cd02128  73 ANAEKLGAVGVLIYPDPADFPIDPSETA----LFGHVHLGT--------------GDPYTPGFPSFN----HtqFPPSQS 130

                       170       180
                ....*....|....*....|....*.
gi 6322586  362 --VPRIPSVPMSARDVQPILERLNGR 385
Cdd:cd02128 131 sgLPNIPAQTISAAAAAKLLSKMGGP 156
M28 cd02690
M28 Zn-peptidases include aminopeptidases and carboxypeptidases; Peptidase M28 family (also ...
 425-609 2.12e-18

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: 84.32  E-value: 2.12e-18
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  425 SSVEVSIPGIFTEGEII-IGAHRDSLASSSAGDAN-SGSAILLEIARGMSKLLKhgwKPLRPIKLISWDGERSGLLGSTD 502
Cdd:cd02690   2 YNVIATIKGSDKPDEVIlIGAHYDSVPLSPGANDNaSGVAVLLELARVLSKLQL---KPKRSIRFAFWDAEELGLLGSKY 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  503 YAEAHAAILRRRALvYLNLDNAISGTNfhckanpllqDVIYEAAKLTEFNGHED-WSLFDHWKYTSNATISLLDGLSSYT 581
Cdd:cd02690  79 YAEQLLSSLKNIRA-ALNLDMIGGAGP----------DLYLQTAPGNDALVEKLlRALAHELENVVYTVVYKEDGGTGGS 147

                       170       180       190
                ....*....|....*....|....*....|
gi 6322586  582 SFQYHL--GVPAAHFQFNANDtSGAVYHSN 609
Cdd:cd02690 148 DHRPFLarGIPAASLIQSESY-NFPYYHTT 176
M28_like cd08015
M28 Zn-peptidase-like; uncharacterized subfamily; Peptidase family M28 (also called ...
 431-561 9.18e-12

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: 65.31  E-value: 9.18e-12
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  431 IPGIFTEGE-IIIGAHRDSL-ASSSAGDANSGSAILLEiarGMSKLLKHGWKPLRPIKLISWDGERSGLLGSTDYAEAHA 508
Cdd:cd08015   8 IPGSDKKDEvVILGAHLDSWhGATGATDNGAGTAVMME---AMRILKAIGSKPKRTIRVALWGSEEQGLHGSRAYVEKHF 84

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 6322586  509 AILRRRAL--------VYLNLDNA------ISGTNFHcKANPLLQDVIYE-----AAKLTEFN-GHEDWSLFD 561
Cdd:cd08015  85 GDPPTMQLqrdhkkisAYFNLDNGtgrirgIYLQGNL-AAYPIFSAWLYPfhdlgATTVIERNtGGTDHAAFD 156
M28_AAP cd03879
M28 Zn-peptidase Aeromonas (Vibrio) proteolytica aminopeptidase; Peptidase family M28; ...
 425-522 7.13e-11

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: 63.80  E-value: 7.13e-11
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  425 SSVEVSIPGIFTEGE-IIIGAHRDSLASSS--------AGDANSGSAILLEIARGmskLLKHGWKPLRPIKLISWDGERS 495
Cdd:cd03879  75 PSIIATIPGSEKSDEiVVIGAHQDSINGSNpsngrapgADDDGSGTVTILEALRV---LLESGFQPKNTIEFHWYAAEEG 151

                        90       100
                ....*....|....*....|....*..
gi 6322586  496 GLLGSTDYAEAHAAiLRRRALVYLNLD 522
Cdd:cd03879 152 GLLGSQAIATQYKS-EGKNVKAMLQLD 177
M28_like_PA cd05661
M28 Zn-peptidase containing a PA domain insert; Peptidase family M28 (also called ...
 440-615 6.21e-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: 60.66  E-value: 6.21e-10
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  440 IIIGAHRDSLASS-SAGDANSGSAILLEIARGMSKLlkhgwKPLRPIKLISWDGERSGLLGSTDYAEAHAAILRRRALVY 518
Cdd:cd05661  79 IIVTSHYDSVVKApGANDNASGTAVTLELARVFKKV-----KTDKELRFIAFGAEENGLLGSKYYVASLSEDEIKRTIGV 153

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  519 LNLDnaISGTNFHCKANPLLQDVIYEAAKLTEFNGHEDWSLFDHWKYTsnatislLDGLSSYTSFqYHLGVPAAHFQFna 598
Cdd:cd05661 154 FNLD--MVGTSDAKAGDLYAYTIDGKPNLVTDSGAAASKRLSGVLPLV-------QQGSSDHVPF-HEAGIPAALFIH-- 221

                       170
                ....*....|....*..
gi 6322586  599 ndTSGAVYHSNSVFDSP 615
Cdd:cd05661 222 --MDPETEPVEPWYHTP 236
PA cd00538
PA: Protease-associated (PA) domain. The PA domain is an insert domain in a diverse fraction ...
 237-304 1.63e-08

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: 53.67  E-value: 1.63e-08
                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 6322586  237 NGSVTARYVFCNYGSISDyklllkKNIDIEDKIHIVRSGKILPGLKVKNAELYGASSVIIYTDPFDDG 304
Cdd:cd00538  23 VGVVAGPLVGCGYGTTDD------SGADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAVIIYNNGDDPG 84
M28_like_PA_PDZ_associated cd05663
M28 Zn-peptidase containing a protease-associated (PA) domain insert and associated with a PDZ ...
 440-594 3.57e-08

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: 55.54  E-value: 3.57e-08
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  440 IIIGAHRD--------SLASSS-------AGDANSGSAILLEIARGMSKLLKHGWKPlRPIKLISWDGERSGLLGSTDYA 504
Cdd:cd05663  73 VVVGAHYDhlgyggegSLARGDeslihngADDNASGVAAMLELAAKLVDSDTSLALS-RNLVFIAFSGEELGLLGSKHFV 151

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  505 EAhAAILRRRALVYLNLDN---------AISGTNfhckANPLLQDVIYEAAKLTEFNGHEDWSLFdhwkytsnatislld 575
Cdd:cd05663 152 KN-PPFPIKNTVYMINMDMvgrlrdnklIVQGTG----TSPGWEQLVQARNKATGFKLILDPTGY--------------- 211

                       170
                ....*....|....*....
gi 6322586  576 GLSSYTSFqYHLGVPAAHF 594
Cdd:cd05663 212 GPSDHTSF-YLDDVPVLHF 229
TFR_dimer pfam04253
Transferrin receptor-like dimerization domain; This domain is involved in dimerization of the ...
 725-799 4.57e-08

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: 51.82  E-value: 4.57e-08
                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 6322586    725 KKIKSYIKLQRSNSKSKQIDQLFITHRGLKDREWMKYSLLAPSKFEGSVGEVLPGLHEGLADIDRNEVIQWLTIL 799
Cdd:pfam04253  30 IKEPDLLAVRAVNDKLMLFERAFLDPEGLPGRPWFKHVVFAPGLWTGYAGATFPGIRDAIEAGDWELAQKQISIV 104
M28_like cd03877
M28 Zn-peptidase, many containing a protease-associated (PA) domain insert; Peptidase family ...
 440-522 6.00e-08

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: 53.79  E-value: 6.00e-08
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  440 IIIGAHRDSL--ASSSAGD-----AN---SGSAILLEIARGmsklLKHGWKPLRPIKLISWDGERSGLLGSTDYAEaHAA 509
Cdd:cd03877  18 IVIGAHYDHLgiGGGDSGDkiyngADdnaSGVAAVLELARY----FAKQKTPKRSIVFAAFTAEEKGLLGSKYFAE-NPK 92

                        90
                ....*....|...
gi 6322586  510 ILRRRALVYLNLD 522
Cdd:cd03877  93 FPLDKIVAMLNLD 105
M28_SGAP_like cd03876
M28 Zn-peptidase Streptomyces griseus aminopeptidase and similar proteins; Peptidase family ...
 440-530 3.97e-07

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: 52.68  E-value: 3.97e-07
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  440 IIIGAHRDSLassSAG----DANSGSAILLEIARGMSKllkhgWKPLRPIKLISWDGERSGLLGSTDYAEAHAAILRRRA 515
Cdd:cd03876  79 VMLGAHLDSV---SAGpginDNGSGSAALLEVALALAK-----FKVKNAVRFAWWTAEEFGLLGSKFYVNNLSSEERSKI 150

                        90
                ....*....|....*
gi 6322586  516 LVYLNLDnAISGTNF 530
Cdd:cd03876 151 RLYLNFD-MIASPNY 164
PA_hNAALADL2_like cd02131
PA_hNAALADL2_like: Protease-associated domain containing proteins like human N-acetylated ...
 234-350 5.69e-07

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: 49.93  E-value: 5.69e-07
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  234 YSKNGSVTARYVFCNYGSISDYKLLlKKNIDIEDKIHIVRSGKiLPGL-KVKNAELYGASSVIIYTDPFDDGKVTEENgf 312
Cdd:cd02131   9 YSAKGTLQAEVVDVQYGSVEDLRRI-RDNMNVTNQIALLKLGQ-APLLyKLSLLEEAGFGGVLLYVDPCDLPKTRHTW-- 84

                        90       100       110
                ....*....|....*....|....*....|....*...
gi 6322586  313 lHYPYGPARNPSyirrdsvnyfsdtpGDPTTPGYPSKD 350
Cdd:cd02131  85 -HQAFMVSLNPG--------------GDPSTPGYPSAD 107
M28_Pgcp_like cd03883
M28 Zn-Peptidase Plasma glutamate carboxypeptidase; Peptidase M28 family; Plasma glutamate ...
 440-548 1.06e-06

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: 51.93  E-value: 1.06e-06
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  440 IIIGAHRDSL-ASSSAGDANSGSAILLEIArgmsKLLKH-GWKPLRPIKLISWDGERSGLLGSTDYAEAHAAILRRRALV 517
Cdd:cd03883 243 VLVGGHLDSWdVGTGAMDDGGGVAISWEAL----KLIKDlGLKPKRTIRVVLWTGEEQGLVGAKAYAEAHKDELENHVFA 318

                        90       100       110
                ....*....|....*....|....*....|.
gi 6322586  518 YLNLDNAISGTNFHCKANPLLQDVIYEAAKL 548
Cdd:cd03883 319 MESDIGTFTPYGLQFTGSDTARAIVKEVMKL 349
M28_like cd05640
M28 Zn-peptidase; uncharacterized subfamily; Peptidase family M28 (also called aminopeptidase ...
 437-506 1.67e-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: 50.52  E-value: 1.67e-06
                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 6322586  437 EGEIIIGAHRDSLASSSAGDAN-SGSAILLEIARgmsklLKHGWKPLRPIKLISWDGE-----RSGLLGSTDYAEA 506
Cdd:cd05640  66 DKLILIGAHYDTVPGSPGADDNaSGVAALLELAR-----LLATLDPNHTLRFVAFDLEeypffARGLMGSHAYAED 136
M28_Fxna_like cd03875
M28 Zn-peptidase Endoplasmic reticulum metallopeptidase 1; Peptidase family M28; Endoplasmic ...
 404-527 2.69e-06

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: 49.89  E-value: 2.69e-06
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  404 PSSSIDKVHLHNELTYNIKEMSSVEVSIPGIFTEGE--IIIGAHRDSLASS-SAGDANSGSAILLEIARGMSkllKHGWK 480
Cdd:cd03875  59 DTGSGSFNFLSSGMTLVYFEVTNIVVRISGKNSNSLpaLLLNAHFDSVPTSpGATDDGMGVAVMLEVLRYLS---KSGHQ 135

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 6322586  481 PLRPIKLISWDGERSGLLGSTDYAEAHaaILRRRALVYLNLDNAISG 527
Cdd:cd03875 136 PKRDIIFLFNGAEENGLLGAHAFITQH--PWAKNVRAFINLEAAGAG 180
M28_like_PA cd05660
M28 Zn-peptidase containing a protease-associated (PA) domain insert; Peptidase family M28 ...
 440-505 3.58e-06

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: 49.67  E-value: 3.58e-06
                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 6322586  440 IIIGAHRDSLA--SSSAGDA--------NSGSAILLEIARGMSKLLKhgwKPLRPIKLISWDGERSGLLGSTDYAE 505
Cdd:cd05660  76 IVLSAHWDHLGigPPIGGDEiyngavdnASGVAAVLELARVFAAQDQ---RPKRSIVFLAVTAEEKGLLGSRYYAA 148
M28_PMSA_TfR_like cd03874
M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor ...
 135-187 4.04e-06

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: 49.22  E-value: 4.04e-06
                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 6322586  135 YLNSLQQENRAKEHVYKYA--GYMSNGASDSSTFKYTLDEFLDMG-YKPKVEKYYP 187
Cdd:cd03874   1 YARKLVDLAKIKEDLEYLSsmPHMAGTKGDAALAKYIENSFKNNGlFEVELEEYSP 56
PA pfam02225
PA domain; The PA (Protease associated) domain is found as an insert domain in diverse ...
 240-319 6.90e-06

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: 45.20  E-value: 6.90e-06
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586    240 VTARYVFCNYGSISDYklllkkniDIEDKIHIVRSGKILPGLKVKNAELYGASSVIIYTDPFDDGKVTEENGFLHYPYGP 319
Cdd:pfam02225   5 VLAPGCYAGDGIPADF--------DVKGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPPGAGGNELYPDGI 76
PRK10199 PRK10199
alkaline phosphatase isozyme conversion aminopeptidase; Provisional
 350-527 7.37e-06

alkaline phosphatase isozyme conversion aminopeptidase; Provisional


Pssm-ID: 182299 [Multi-domain]  Cd Length: 346  Bit Score: 48.97  E-value: 7.37e-06
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586   350 DSDTEHMSPV--GRVPRIPSVPMSArdvqpilERLNGRGFQIGPGSNIKDFGSFTGPSSSIDKVHLHNeLTynikeMSSV 427
Cdd:PRK10199  34 NTQARHIATFfpGRMTGSPAEMLSA-------DYLRQQFQQMGYQSDIRTFNSRYIYTARDNRKNWHN-VT-----GSTV 100

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586   428 ----EVSIPGiftegEIIIGAHRDSLASSSAGDAN---------------SGSAILLEIARGMSKllkhgwKPLR-PIKL 487
Cdd:PRK10199 101 iaahEGKAPQ-----QIIIMAHLDTYAPQSDADVDanlggltlqgmddnaAGLGVMLELAERLKN------VPTEyGIRF 169

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 6322586   488 ISWDGERSGLLGSTDYAEAHAAILRRRALVYLNLDNAISG 527
Cdd:PRK10199 170 VATSGEEEGKLGAENLLKRMSDTEKKNTLLVINLDNLIVG 209
PA_C5a_like cd02133
PA_C5a_like: Protease-associated domain containing proteins like Streptococcus pyogenes C5a ...
 241-297 7.64e-04

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: 40.73  E-value: 7.64e-04
                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 6322586  241 TARYVFCNYGSISDYKlllkkNIDIEDKIHIVRSGKILPGLKVKNAELYGASSVIIY 297
Cdd:cd02133  27 TYELVDAGLGTPEDFE-----GKDVKGKIALIQRGEITFVEKIANAKAAGAVGVIIY 78
M28_like cd05643
M28 Zn-peptidase-like; Peptidase family M28 (also called aminopeptidase Y family), ...
 378-475 5.66e-03

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: 39.70  E-value: 5.66e-03
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6322586  378 ILERLNGRGFQIGPGSNIKDFGS-----FTGPSSSIDKVHLHNELTynikemssVEVSIPGIFTEGEIIIGAHrdsLASS 452
Cdd:cd05643  27 VKELLEELGLEAKLISDIYDGGEriltpQSPISWELIEGELNETLP--------ILYAIIGKETPPEIAFVAH---LCHP 95

                        90       100
                ....*....|....*....|....*
gi 6322586  453 SAG--DANSGSAILLEIARGMSKLL 475
Cdd:cd05643  96 KPGanDNASGSALLLEVARVLAKLI 120
 
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.
Help | Disclaimer | Write to the Help Desk
NCBI | NLM | NIH