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Conserved domains on  [gi|1009287619|ref|NP_001308392|]
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BOS complex subunit NCLN isoform 2 precursor [Homo sapiens]

Protein Classification

nicalin-like protein( domain architecture ID 10133856)

nicalin-like protein, similar to Human nicalin which regulates assembly and stability of the nicalin-nodal modulator (NOMO) membrane protein complex

Graphical summary

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List of domain hits

 Name Accession Description Interval E-value
M28_nicalin_like cd03882
M28 Zn-Peptidase Nicalin, Nicastrin-like protein; Peptidase M28 family, Nicalin ...
 127-429 1.82e-157

M28 Zn-Peptidase Nicalin, Nicastrin-like protein; Peptidase M28 family, Nicalin (nicastrin-like protein) subfamily. Nicalin is distantly related to Nicastrin, a component of the Alzheimer's disease-associated gamma-secretase, and forms a complex with Nomo (nodal modulator) pM5. Similar to Nicastrin, Nicalin lacks the amino-acid conservation required for catalytically active aminopeptidases. Functional studies in zebrafish embryos and cultured human cells reveal that nicalin and Nomo collaborate to antagonize the Nodal/TGFbeta signaling pathway. Thus, nicastrin and nicalin are both associated with protein complexes involved in cell fate decisions during early embryonic development.


:

Pssm-ID: 349878  Cd Length: 296  Bit Score: 451.44  E-value: 1.82e-157
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 127 FMEIEPEMLAMETAVPVYFAVEDEALLSIYKQTQAASASQGSASaaEVLLRTATANGFQMVTSGVQSKAVSDWLIASVEG 206
Cdd:cd03882     1 FMELEAELLNTKTNVPVYFAPENEELLSIYEDVKSSSAAAQSAA--EVLIRSLSANGFKIVVSGNSPKAISDWKITTIEG 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 207 RLTGLG-GEDLPTIVIVAHYDAFGVAPWLSLGADSNGSGVSVLLELARLFSRLYTYKRTHAAYNLLFFASGGGKFNYQGT 285
Cdd:cd03882    79 RLTGLGdGEKLPTIVIVAHYDTFGVAPWLSSGADSNGSGVAALLELMRLFSRLYSNPRTRAKYNLLFLLTGGGKLNYQGT 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 286 KRWLEDNLDHTdssllQDNVAFVLCLDTVGRGSS-LHLHVSKPPREGTLQHAFLRELETVAAHqfPEVRFSMVHKRINLA 364
Cdd:cd03882   159 KHWLESNLDHF-----LDNVEFVLCLDSIGSKDSdLYLHVSKPPKEGTHIQQFLEELKSVAKA--PDKNLTVVHKKINLA 231

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1009287619 365 EDVLAWEHERFAIRRLPAFTLSHLESHRDGQRSSIMDVRSRVDSKTLTRNTRIIAEALTRVIYNL 429
Cdd:cd03882   232 DTKLAWEHERFSIKRLPAFTLSHLESHRSPLRNSIFDTRSSVDEDKLKRNTKIIAEALARYIYNL 296
 
Name Accession Description Interval E-value
M28_nicalin_like cd03882
M28 Zn-Peptidase Nicalin, Nicastrin-like protein; Peptidase M28 family, Nicalin ...
 127-429 1.82e-157

M28 Zn-Peptidase Nicalin, Nicastrin-like protein; Peptidase M28 family, Nicalin (nicastrin-like protein) subfamily. Nicalin is distantly related to Nicastrin, a component of the Alzheimer's disease-associated gamma-secretase, and forms a complex with Nomo (nodal modulator) pM5. Similar to Nicastrin, Nicalin lacks the amino-acid conservation required for catalytically active aminopeptidases. Functional studies in zebrafish embryos and cultured human cells reveal that nicalin and Nomo collaborate to antagonize the Nodal/TGFbeta signaling pathway. Thus, nicastrin and nicalin are both associated with protein complexes involved in cell fate decisions during early embryonic development.


Pssm-ID: 349878  Cd Length: 296  Bit Score: 451.44  E-value: 1.82e-157
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 127 FMEIEPEMLAMETAVPVYFAVEDEALLSIYKQTQAASASQGSASaaEVLLRTATANGFQMVTSGVQSKAVSDWLIASVEG 206
Cdd:cd03882     1 FMELEAELLNTKTNVPVYFAPENEELLSIYEDVKSSSAAAQSAA--EVLIRSLSANGFKIVVSGNSPKAISDWKITTIEG 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 207 RLTGLG-GEDLPTIVIVAHYDAFGVAPWLSLGADSNGSGVSVLLELARLFSRLYTYKRTHAAYNLLFFASGGGKFNYQGT 285
Cdd:cd03882    79 RLTGLGdGEKLPTIVIVAHYDTFGVAPWLSSGADSNGSGVAALLELMRLFSRLYSNPRTRAKYNLLFLLTGGGKLNYQGT 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 286 KRWLEDNLDHTdssllQDNVAFVLCLDTVGRGSS-LHLHVSKPPREGTLQHAFLRELETVAAHqfPEVRFSMVHKRINLA 364
Cdd:cd03882   159 KHWLESNLDHF-----LDNVEFVLCLDSIGSKDSdLYLHVSKPPKEGTHIQQFLEELKSVAKA--PDKNLTVVHKKINLA 231

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1009287619 365 EDVLAWEHERFAIRRLPAFTLSHLESHRDGQRSSIMDVRSRVDSKTLTRNTRIIAEALTRVIYNL 429
Cdd:cd03882   232 DTKLAWEHERFSIKRLPAFTLSHLESHRSPLRNSIFDTRSSVDEDKLKRNTKIIAEALARYIYNL 296
Iap COG2234
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein ...
 173-425 2.12e-15

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: 76.32  E-value: 2.12e-15
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 173 EVLLRTATANGFQMVTSGVQSKAVSDWLIASVEGRLTGLGGEDlPTIVIVAHYDAFGVapwLSLGADSNGSGVSVLLELA 252
Cdd:COG2234    18 AAAAAAAAAAGLALLKLKGLLLEAAGGDSRNVIAEIPGTDPPD-EVVVLGAHYDSVGS---IGPGADDNASGVAALLELA 93

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 253 RLFSRL-YTYKRThaaynLLFFASGGGKFNYQGTKRWLEDNLDhtdsslLQDNVAFVLCLDTVGRGS---SLHLHVSKPP 328
Cdd:COG2234    94 RALAALgPKPKRT-----IRFVAFGAEEQGLLGSRYYAENLKA------PLEKIVAVLNLDMIGRGGprnYLYVDGDGGS 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 329 REgtlqhaFLRELETVAAHQFPEVRFSMVHKRinlaEDVLAWEHERFAIRRLPAFTLSHLESHRDGQRSSIMDVRSRVDS 408
Cdd:COG2234   163 PE------LADLLEAAAKAYLPGLGVDPPEET----GGYGRSDHAPFAKAGIPALFLFTGAEDYHPDYHTPSDTLDKIDL 232

                         250
                  ....*....|....*..
gi 1009287619 409 KTLTRNTRIIAEALTRV 425
Cdd:COG2234   233 DALAKVAQLLAALVYEL 249
Peptidase_M28 pfam04389
Peptidase family M28;
211-351 1.09e-11

Peptidase family M28;


Pssm-ID: 461288 [Multi-domain]  Cd Length: 192  Bit Score: 63.84  E-value: 1.09e-11
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 211 LGGEDLPTIVIV-AHYDAFGVAPwlslGADSNGSGVSVLLELARLFSRLYTYKRThaaynLLFFASGGGKFNYQGTKRWL 289
Cdd:pfam04389   6 LPGKAPDEVVLLsAHYDSVGTGP----GADDNASGVAALLELARVLAAGQRPKRS-----VRFLFFDAEEAGLLGSHHFA 76

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1009287619 290 EDNLDhtdssllQDNVAFVLCLDTVGRGSSLHLHVS----KPPREGTLQHAFLRELETVAAHQFPE 351
Cdd:pfam04389  77 KSHPP-------LKKIRAVINLDMIGSGGPALLFQSgpkgSSLLEKYLKAAAKPYGVTLAEDPFQE 135
PRK10199 PRK10199
alkaline phosphatase isozyme conversion aminopeptidase; Provisional
 219-289 2.63e-03

alkaline phosphatase isozyme conversion aminopeptidase; Provisional


Pssm-ID: 182299 [Multi-domain]  Cd Length: 346  Bit Score: 40.11  E-value: 2.63e-03
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 219 IVIVAHYDAFgvAPW-----------LSL-GADSNGSGVSVLLELARlfsRLytyKRTHAAYNLLFFASGGGKFNYQGTK 286
Cdd:PRK10199  112 IIIMAHLDTY--APQsdadvdanlggLTLqGMDDNAAGLGVMLELAE---RL---KNVPTEYGIRFVATSGEEEGKLGAE 183


                  ...
gi 1009287619 287 RWL 289
Cdd:PRK10199  184 NLL 186
 
Name Accession Description Interval E-value
M28_nicalin_like cd03882
M28 Zn-Peptidase Nicalin, Nicastrin-like protein; Peptidase M28 family, Nicalin ...
 127-429 1.82e-157

M28 Zn-Peptidase Nicalin, Nicastrin-like protein; Peptidase M28 family, Nicalin (nicastrin-like protein) subfamily. Nicalin is distantly related to Nicastrin, a component of the Alzheimer's disease-associated gamma-secretase, and forms a complex with Nomo (nodal modulator) pM5. Similar to Nicastrin, Nicalin lacks the amino-acid conservation required for catalytically active aminopeptidases. Functional studies in zebrafish embryos and cultured human cells reveal that nicalin and Nomo collaborate to antagonize the Nodal/TGFbeta signaling pathway. Thus, nicastrin and nicalin are both associated with protein complexes involved in cell fate decisions during early embryonic development.


Pssm-ID: 349878  Cd Length: 296  Bit Score: 451.44  E-value: 1.82e-157
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 127 FMEIEPEMLAMETAVPVYFAVEDEALLSIYKQTQAASASQGSASaaEVLLRTATANGFQMVTSGVQSKAVSDWLIASVEG 206
Cdd:cd03882     1 FMELEAELLNTKTNVPVYFAPENEELLSIYEDVKSSSAAAQSAA--EVLIRSLSANGFKIVVSGNSPKAISDWKITTIEG 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 207 RLTGLG-GEDLPTIVIVAHYDAFGVAPWLSLGADSNGSGVSVLLELARLFSRLYTYKRTHAAYNLLFFASGGGKFNYQGT 285
Cdd:cd03882    79 RLTGLGdGEKLPTIVIVAHYDTFGVAPWLSSGADSNGSGVAALLELMRLFSRLYSNPRTRAKYNLLFLLTGGGKLNYQGT 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 286 KRWLEDNLDHTdssllQDNVAFVLCLDTVGRGSS-LHLHVSKPPREGTLQHAFLRELETVAAHqfPEVRFSMVHKRINLA 364
Cdd:cd03882   159 KHWLESNLDHF-----LDNVEFVLCLDSIGSKDSdLYLHVSKPPKEGTHIQQFLEELKSVAKA--PDKNLTVVHKKINLA 231

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1009287619 365 EDVLAWEHERFAIRRLPAFTLSHLESHRDGQRSSIMDVRSRVDSKTLTRNTRIIAEALTRVIYNL 429
Cdd:cd03882   232 DTKLAWEHERFSIKRLPAFTLSHLESHRSPLRNSIFDTRSSVDEDKLKRNTKIIAEALARYIYNL 296
M28 cd02690
M28 Zn-peptidases include aminopeptidases and carboxypeptidases; Peptidase M28 family (also ...
 201-425 7.78e-53

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: 178.69  E-value: 7.78e-53
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 201 IASVEGRLTGLGGEDlPTIVIVAHYDAFGVAPwlslGADSNGSGVSVLLELARLFSRLYtyKRTHAAYNLLFFASGGGKf 280
Cdd:cd02690     1 GYNVIATIKGSDKPD-EVILIGAHYDSVPLSP----GANDNASGVAVLLELARVLSKLQ--LKPKRSIRFAFWDAEELG- 72

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 281 nYQGTKRWLEDNLDHtdssllQDNVAFVLCLDTVGRGSSlHLHVSKPPREGTLQHAFLRELETVAAHQFPEVRFsmvhkr 360
Cdd:cd02690    73 -LLGSKYYAEQLLSS------LKNIRAALNLDMIGGAGP-DLYLQTAPGNDALVEKLLRALAHELENVVYTVVY------ 138

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1009287619 361 iNLAEDVLAWEHERFAIRRLPAFTLSHLESHRDGQRSSIMDVRSRVDSKTLTRNTRIIAEALTRV 425
Cdd:cd02690   139 -KEDGGTGGSDHRPFLARGIPAASLIQSESYNFPYYHTTQDTLENIDKDTLKRAGDILASFLYRL 202
Iap COG2234
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein ...
 173-425 2.12e-15

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: 76.32  E-value: 2.12e-15
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 173 EVLLRTATANGFQMVTSGVQSKAVSDWLIASVEGRLTGLGGEDlPTIVIVAHYDAFGVapwLSLGADSNGSGVSVLLELA 252
Cdd:COG2234    18 AAAAAAAAAAGLALLKLKGLLLEAAGGDSRNVIAEIPGTDPPD-EVVVLGAHYDSVGS---IGPGADDNASGVAALLELA 93

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 253 RLFSRL-YTYKRThaaynLLFFASGGGKFNYQGTKRWLEDNLDhtdsslLQDNVAFVLCLDTVGRGS---SLHLHVSKPP 328
Cdd:COG2234    94 RALAALgPKPKRT-----IRFVAFGAEEQGLLGSRYYAENLKA------PLEKIVAVLNLDMIGRGGprnYLYVDGDGGS 162

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 329 REgtlqhaFLRELETVAAHQFPEVRFSMVHKRinlaEDVLAWEHERFAIRRLPAFTLSHLESHRDGQRSSIMDVRSRVDS 408
Cdd:COG2234   163 PE------LADLLEAAAKAYLPGLGVDPPEET----GGYGRSDHAPFAKAGIPALFLFTGAEDYHPDYHTPSDTLDKIDL 232

                         250
                  ....*....|....*..
gi 1009287619 409 KTLTRNTRIIAEALTRV 425
Cdd:COG2234   233 DALAKVAQLLAALVYEL 249
M28_like_PA_PDZ_associated cd05663
M28 Zn-peptidase containing a protease-associated (PA) domain insert and associated with a PDZ ...
 204-392 1.98e-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: 1.98e-12
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 204 VEGRLTGLGGEDLPTIVIVAHYDAFG------VAPWLSL----GADSNGSGVSVLLELARLFSRLYTYKRTHAayNLLFF 273
Cdd:cd05663    58 VIGVLPGKGDVADETVVVGAHYDHLGyggegsLARGDESlihnGADDNASGVAAMLELAAKLVDSDTSLALSR--NLVFI 135

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 274 ASGGGKFNYQGTKRWLEdnldhtDSSLLQDNVAFVLCLDTVGRGSSLHLHV----SKPPREGTLQHaflreletvaahqf 349
Cdd:cd05663   136 AFSGEELGLLGSKHFVK------NPPFPIKNTVYMINMDMVGRLRDNKLIVqgtgTSPGWEQLVQA-------------- 195

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 1009287619 350 pevRFSMVHKRINLAED-VLAWEHERFAIRRLPA---FTLSHLESHR 392
Cdd:cd05663   196 ---RNKATGFKLILDPTgYGPSDHTSFYLDDVPVlhfFTGAHSDYHR 239
Peptidase_M28 pfam04389
Peptidase family M28;
211-351 1.09e-11

Peptidase family M28;


Pssm-ID: 461288 [Multi-domain]  Cd Length: 192  Bit Score: 63.84  E-value: 1.09e-11
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 211 LGGEDLPTIVIV-AHYDAFGVAPwlslGADSNGSGVSVLLELARLFSRLYTYKRThaaynLLFFASGGGKFNYQGTKRWL 289
Cdd:pfam04389   6 LPGKAPDEVVLLsAHYDSVGTGP----GADDNASGVAALLELARVLAAGQRPKRS-----VRFLFFDAEEAGLLGSHHFA 76

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1009287619 290 EDNLDhtdssllQDNVAFVLCLDTVGRGSSLHLHVS----KPPREGTLQHAFLRELETVAAHQFPE 351
Cdd:pfam04389  77 KSHPP-------LKKIRAVINLDMIGSGGPALLFQSgpkgSSLLEKYLKAAAKPYGVTLAEDPFQE 135
M28_PMSA_TfR_like cd03874
M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor ...
 201-344 1.07e-09

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: 59.62  E-value: 1.07e-09
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 201 IASVEGRLTGLGGEDLpTIVIVAHYDAFGVapwlslGADSNGSGVSVLLELARLFSRLyTYK------RThaaynlLFFA 274
Cdd:cd03874    57 ITNVVGKIEGIEQPDR-AIIIGAHRDSWGY------GAGYPNSGTAVLLEIARLFQQL-KKKfgwkplRT------IYFI 122

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1009287619 275 S-GGGKFNYQGTKRWLEDNLDhtdssLLQDNVAFVLCLDTVGRGSSlHLHVSKPPregTLQHAFLRELETV 344
Cdd:cd03874   123 SwDGSEFGLAGSTELGEDRKA-----SLKDEVYAYINIDQLVIGNS-ELDVDAHP---LLQSLFRKASKKV 184
M28_like cd03877
M28 Zn-peptidase, many containing a protease-associated (PA) domain insert; Peptidase family ...
 211-274 4.88e-09

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: 56.48  E-value: 4.88e-09
                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1009287619 211 LGGEDLP--TIVIVAHYDAFGVAPWLSL-----GADSNGSGVSVLLELARLFSRLYTYKRthaayNLLFFA 274
Cdd:cd03877     8 LEGSDLPdeTIVIGAHYDHLGIGGGDSGdkiynGADDNASGVAAVLELARYFAKQKTPKR-----SIVFAA 73
M28_like cd05640
M28 Zn-peptidase; uncharacterized subfamily; Peptidase family M28 (also called aminopeptidase ...
 192-315 1.78e-08

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: 55.92  E-value: 1.78e-08
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 192 QSKAVSDWLIASVEGRLTGLGGEDlPTIVIVAHYDAFGVAPwlslGADSNGSGVSVLLELARLFSRLytykrtHAAYNLL 271
Cdd:cd05640    43 HFFSHQEGVYANLIADLPGSYSQD-KLILIGAHYDTVPGSP----GADDNASGVAALLELARLLATL------DPNHTLR 111

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1009287619 272 FFAsgggkFN---YQGTKRWLEDNLDHTDSSLLQDN-VAFVLCLDTVG 315
Cdd:cd05640   112 FVA-----FDleeYPFFARGLMGSHAYAEDLLRPLTpIVGMLSLEMIG 154
M28_PSMA_like cd08022
M28 Zn-peptidase prostate-specific membrane antigen; Peptidase M28 family; prostate-specific ...
 201-321 6.27e-08

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: 54.16  E-value: 6.27e-08
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 201 IASVEGRLTGLGGEDlPTIVIVAHYDAfgvapWlSLGA-DSNgSGVSVLLELARLFSRL----YTYKRThaaynlLFFAS 275
Cdd:cd08022    60 IWNVIGTIRGSEEPD-EYIILGNHRDA-----W-VFGAgDPN-SGTAVLLEVARALGTLlkkgWRPRRT------IIFAS 125

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1009287619 276 -GGGKFNYQGTKRWLEDNLDhtdssLLQDNVAFVLCLDTVGRGSSLH 321
Cdd:cd08022   126 wDAEEYGLIGSTEWVEENAD-----WLQERAVAYLNVDVAVSGSTLR 167
Nicastrin pfam05450
Nicastrin; Nicastrin and presenilin are two major components of the gamma-secretase complex, ...
 217-326 6.58e-06

Nicastrin; Nicastrin and presenilin are two major components of the gamma-secretase complex, which executes the intramembrane proteolysis of type I integral membrane proteins such as the amyloid precursor protein (APP) and Notch. Nicastrin is synthesized in fibroblasts and neurons as an endoglycosidase-H-sensitive glycosylated precursor protein (immature nicastrin) and is then modified by complex glycosylation in the Golgi apparatus and by sialylation in the trans-Golgi network (mature nicastrin). A region featured in this family has a fold similar to human transferrin receptor (TfR) and a bacterial aminopeptidase. It is implicated in the pathogenesis of Alzheimer's disease.


Pssm-ID: 310213 [Multi-domain]  Cd Length: 227  Bit Score: 47.54  E-value: 6.58e-06
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 217 PTIVIVAHYDAFGVAPWLSLGADSNGSGVSVLLELARLFSRLY----TYKRthaayNLLFFASGGGKFNYQGTKRWLEDN 292
Cdd:pfam05450   1 KVVLVTARMDSTSMFDGVSLGAMSSLSGFIVLLAAADALSKALpdisNLKR-----NVLFAFFNGESYDYIGSQRFVYDM 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1009287619 293 LDHTDSS-------LLQDNVAFVLCLDTVGRGSS--LHLHVSK 326
Cdd:pfam05450  76 ENGKFPSdrththpISPDNIDYMLEIGQVGKATSrkFYLHVDA 118
M28_like cd05643
M28 Zn-peptidase-like; Peptidase family M28 (also called aminopeptidase Y family), ...
 212-355 8.64e-06

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: 47.78  E-value: 8.64e-06
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 212 GGEDLPTIVIVAHydAFGVAPwlslGADSNGSGVSVLLELARLFSRLYTyKRTHAAYNLLFFASgggkfnYQGTKRWLED 291
Cdd:cd05643    79 GKETPPEIAFVAH--LCHPKP----GANDNASGSALLLEVARVLAKLIL-NRPKRGICFLWVPE------YTGTAAYFAQ 145

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1009287619 292 NLDHtdssllQDNVAFVLCLDTVGR-----GSSLHLHVSKPPREGTLQHAFLRELETVAAHQFPEVRFS 355
Cdd:cd05643   146 HPDR------LKKIIAVINLDMVGEdqtktGSTLMLVPTPLSFPSYLNEELAQKLSNFTGSSLPAVRYG 208
M28_like_PA cd05661
M28 Zn-peptidase containing a PA domain insert; Peptidase family M28 (also called ...
 217-262 9.71e-06

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: 47.57  E-value: 9.71e-06
                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1009287619 217 PTIVIVAHYDAFGVAPwlslGADSNGSGVSVLLELARLFSRLYTYK 262
Cdd:cd05661    77 DIIIVTSHYDSVVKAP----GANDNASGTAVTLELARVFKKVKTDK 118
M28_Nicastrin cd03881
M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, ...
 217-334 1.17e-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: 48.19  E-value: 1.17e-05
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 217 PTIVIVAHYDAFGVAPWLSLGADSNGSGVSVLLELARLFSRL---YTYKRthaayNLLFFASGGGKFNYQGTKRWLEDNL 293
Cdd:cd03881   211 KIVLVAARMDSTSFFRDVAPGADSSLSGFVALLAAAEALKKVdgkGSLKR-----NVVFAFFNGESWGYIGSSRFVYDME 285

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1009287619 294 DHTDSSLL-----------QDNVAFVLCLDTVGR--GSSLHLHVSKPPREGTLQ 334
Cdd:cd03881   286 NGKFPTYGskddlfffpisFENIDTILEVGQVGLalGAKLYAHTDGVSTNSSVT 339
M28_like_PA cd05660
M28 Zn-peptidase containing a protease-associated (PA) domain insert; Peptidase family M28 ...
 211-256 2.68e-05

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: 46.20  E-value: 2.68e-05
                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1009287619 211 LGGEDLP--TIVIVAHYDAFGVAPWLS-----LGADSNGSGVSVLLELARLFS 256
Cdd:cd05660    66 LPGSKLPdeYIVLSAHWDHLGIGPPIGgdeiyNGAVDNASGVAAVLELARVFA 118
M28_AAP cd03879
M28 Zn-peptidase Aeromonas (Vibrio) proteolytica aminopeptidase; Peptidase family M28; ...
 203-264 3.24e-04

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: 43.00  E-value: 3.24e-04
                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 203 SVEGRLTGlGGEDLPTIVIVAHYD-------AFGVAPwlslGADSNGSGVSVLLELAR-LFSRLYTYKRT 264
Cdd:cd03879    76 SIIATIPG-SEKSDEIVVIGAHQDsingsnpSNGRAP----GADDDGSGTVTILEALRvLLESGFQPKNT 140
M28_TfR cd09848
M28 Zn-peptidase Transferrin Receptor family; Peptidase M28 family; Transferrin Receptor (TfR) ...
 219-328 4.32e-04

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: 42.36  E-value: 4.32e-04
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 219 IVIVAHYDAFGVapwlslGADSNGSGVSVLLELARLFSRL-----YTYKRThaaynlLFFAS-GGGKFNYQGTKRWLEDN 292
Cdd:cd09848    73 VVIGAQRDAWGP------GAAKSGVGTALLLELARTFSDMvkndgFKPRRS------IVFASwSAGDFGSVGATEWLEGY 140

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1009287619 293 LdhtdSSLLQDNVAFVlCLDTVGRGSSlHLHVSKPP 328
Cdd:cd09848   141 L----SSLHLKAFTYI-SLDGAVLGDD-SFKASASP 170
M28_like cd05662
M28 Zn-Peptidases; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized ...
 213-274 5.00e-04

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: 42.07  E-value: 5.00e-04
                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1009287619 213 GEDLPT--IVIVAHYDAFGV-APWLSLGADSNGSGVSVLLELARlfsrlytYKRTHAA-YNLLFFA 274
Cdd:cd05662    71 GSEPPTkwRVVSAHYDHLGIrGGKIYNGADDNASGVAALLALAE-------YFKKHPPkHNVIFAA 129
M28_Fxna_like cd03875
M28 Zn-peptidase Endoplasmic reticulum metallopeptidase 1; Peptidase family M28; Endoplasmic ...
 207-257 6.81e-04

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: 41.80  E-value: 6.81e-04
                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1009287619 207 RLTGLGGEDLPTIVIVAHYDafGVAPwlSLGADSNGSGVSVLLELARLFSR 257
Cdd:cd03875    85 RISGKNSNSLPALLLNAHFD--SVPT--SPGATDDGMGVAVMLEVLRYLSK 131
PRK10199 PRK10199
alkaline phosphatase isozyme conversion aminopeptidase; Provisional
 219-289 2.63e-03

alkaline phosphatase isozyme conversion aminopeptidase; Provisional


Pssm-ID: 182299 [Multi-domain]  Cd Length: 346  Bit Score: 40.11  E-value: 2.63e-03
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1009287619 219 IVIVAHYDAFgvAPW-----------LSL-GADSNGSGVSVLLELARlfsRLytyKRTHAAYNLLFFASGGGKFNYQGTK 286
Cdd:PRK10199  112 IIIMAHLDTY--APQsdadvdanlggLTLqGMDDNAAGLGVMLELAE---RL---KNVPTEYGIRFVATSGEEEGKLGAE 183


                  ...
gi 1009287619 287 RWL 289
Cdd:PRK10199  184 NLL 186
 
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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