M28 Zn-peptidase Streptomyces griseus aminopeptidase and similar proteins; Peptidase family M28; Streptomyces griseus Aminopeptidase (SGAP, Leucine aminopeptidase (LAP), aminopeptidase S, Mername-AA022 peptidase) subfamily. SGAP is a di-zinc exopeptidase with high preference towards large hydrophobic amino-terminal residues, with Leu being the most efficiently cleaved. It can accommodate all except Pro and Glu residues in the P1' position. It is a monomeric (30 kDa), calcium-activated and calcium-stabilized enzyme; its activation by calcium correlates with substrate specificity and it has thermal stability only in the presence of calcium. Although SGAP contains a calcium binding site, it is not conserved in many members of this subfamily. SGAP is present in the extracellular fluid of S. griseus cultures.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241  78 KIKVDDLNATAWDLYRLAnystpDYGHPTRVIGSKGHNKTMEYILNVFDDMqDYYDVSLQEFEALsgkiisfnlsdaetg 157
Cdd:cd03876   1 DITVDNLMAHLQQLQDIA-----DANGGNRAFGSPGYNASVDYVKNELKAA-GYYDVTLQPFTSL--------------- 59

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 158 ksfanttafalsppvdgfvgklveipnlgceekdyasvvpprhnekqialiergkcpfgdksnlagkfgftavviydnep 237
Cdd:cd03876     --------------------------------------------------------------------------------

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 238 kskeglhgtlgeptkhtvatvgvpykvgkklianialnidyslyfamdsyveFIKTQNIIADTKHGDPDNIVALGAHSDS 317
Cdd:cd03876  60 ----------------------------------------------------YRTTYNVIAETKGGDPNNVVMLGAHLDS 87

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 318 VEEGPGINDDGSGTISLLNVAKQLTHFKINNKVRFAWWAAEEEGLLGSNFYAYNLTKEENSKIRVFMDYDMMASPNYEYE 397
Cdd:cd03876  88 VSAGPGINDNGSGSAALLEVALALAKFKVKNAVRFAWWTAEEFGLLGSKFYVNNLSSEERSKIRLYLNFDMIASPNYGYF 167

                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 398 IYDANNKEN----PKGSEELKNLYVDYYKAHHLNYTLVPFDGRSDYVGFINNGIPAGGIATGAEKNNV---------NNG 464
Cdd:cd03876 168 IYDGDGSAFnltgPPGSAEIERLFEAYFTSLGLPSTPTEFDGRSDYAPFIEAGIPAGGLFTGAEGIKTeeqaalwggTAG 247

                       410       420       430       440
                ....*....|....*....|....*....|....*....|..
gi 82795241 465 KVLDRCYHQLCDDVSNLSWDAFITNTKLIAHSVATYADSFEG 506
Cdd:cd03876 248 VAYDPCYHQACDTIDNINRTALLRNADAIAHAVATYARSTEG 289

M28 Zn-peptidase Streptomyces griseus aminopeptidase and similar proteins; Peptidase family M28; Streptomyces griseus Aminopeptidase (SGAP, Leucine aminopeptidase (LAP), aminopeptidase S, Mername-AA022 peptidase) subfamily. SGAP is a di-zinc exopeptidase with high preference towards large hydrophobic amino-terminal residues, with Leu being the most efficiently cleaved. It can accommodate all except Pro and Glu residues in the P1' position. It is a monomeric (30 kDa), calcium-activated and calcium-stabilized enzyme; its activation by calcium correlates with substrate specificity and it has thermal stability only in the presence of calcium. Although SGAP contains a calcium binding site, it is not conserved in many members of this subfamily. SGAP is present in the extracellular fluid of S. griseus cultures.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241  78 KIKVDDLNATAWDLYRLAnystpDYGHPTRVIGSKGHNKTMEYILNVFDDMqDYYDVSLQEFEALsgkiisfnlsdaetg 157
Cdd:cd03876   1 DITVDNLMAHLQQLQDIA-----DANGGNRAFGSPGYNASVDYVKNELKAA-GYYDVTLQPFTSL--------------- 59

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 158 ksfanttafalsppvdgfvgklveipnlgceekdyasvvpprhnekqialiergkcpfgdksnlagkfgftavviydnep 237
Cdd:cd03876     --------------------------------------------------------------------------------

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 238 kskeglhgtlgeptkhtvatvgvpykvgkklianialnidyslyfamdsyveFIKTQNIIADTKHGDPDNIVALGAHSDS 317
Cdd:cd03876  60 ----------------------------------------------------YRTTYNVIAETKGGDPNNVVMLGAHLDS 87

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 318 VEEGPGINDDGSGTISLLNVAKQLTHFKINNKVRFAWWAAEEEGLLGSNFYAYNLTKEENSKIRVFMDYDMMASPNYEYE 397
Cdd:cd03876  88 VSAGPGINDNGSGSAALLEVALALAKFKVKNAVRFAWWTAEEFGLLGSKFYVNNLSSEERSKIRLYLNFDMIASPNYGYF 167

                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 398 IYDANNKEN----PKGSEELKNLYVDYYKAHHLNYTLVPFDGRSDYVGFINNGIPAGGIATGAEKNNV---------NNG 464
Cdd:cd03876 168 IYDGDGSAFnltgPPGSAEIERLFEAYFTSLGLPSTPTEFDGRSDYAPFIEAGIPAGGLFTGAEGIKTeeqaalwggTAG 247

                       410       420       430       440
                ....*....|....*....|....*....|....*....|..
gi 82795241 465 KVLDRCYHQLCDDVSNLSWDAFITNTKLIAHSVATYADSFEG 506
Cdd:cd03876 248 VAYDPCYHQACDTIDNINRTALLRNADAIAHAVATYARSTEG 289

PA_ScAPY_like: Protease-associated domain containing proteins like Saccharomyces cerevisiae aminopeptidase Y (ScAPY). This group contains various PA domain-containing proteins similar to the S. cerevisiae APY, including Trichophyton rubrum leucine aminopeptidase 1(LAP1). Proteins in this group belong to the peptidase M28 family. ScAPY hydrolyzes amino acid-4-methylcoumaryl-7-amides (MCAs). ScAPY more rapidly hydrolyzes dipeptidyl-MCAs. Hydrolysis of amino acid-MCAs or dipeptides is stimulated by Co2+ while the hydrolysis of dipeptidyl-MCAs, tripeptides, and longer peptides is inhibited by Co2+. ScAPY is vacuolar and is activated by proteolytic processing. LAP1 is a secreted leucine aminopeptidase. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 155 ETGKSFANTTAFALSPPVDGFvGKLVEIPNLGCEEKDYASVVpprhnEKQIALIERGKCPFGDKSNLAGKFGFTAVVIYD 234
Cdd:cd02130   3 SANGEAIPTTAFTYSPAGEVT-GPLVVVPNLGCDAADYPASV-----AGNIALIERGECPFGDKSALAGAAGAAAAIIYN 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 82795241 235 NEPksKEGLHGTLGEPTKHTVATVGVPYKVGKKLIANIALniDYSLYFAM 284
Cdd:cd02130  77 NVP--AGGLSGTLGEPSGPYVPTVGISQEDGKALVAALAN--GGEVSANL 122

PA domain; The PA (Protease associated) domain is found as an insert domain in diverse proteases. The PA domain is also found in a plant vacuolar sorting receptor Swiss:O22925 and members of the RZF family Swiss:O43567. It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241   177 GKLVEIPnlGCEEKDYASvvPPRHNEKQIALIERGKCPFGDKSNLAGKFGFTAVVIYDNEPKSKEGLH--GTLGEPTKHT 254
Cdd:pfam02225   2 GPLVLAP--GCYAGDGIP--ADFDVKGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPPGagGNELYPDGIY 77

                          90
                  ....*....|....
gi 82795241   255 VATVGVPYKVGKKL 268
Cdd:pfam02225  78 IPAVGVSRADGEAL 91

M28 Zn-peptidase Streptomyces griseus aminopeptidase and similar proteins; Peptidase family M28; Streptomyces griseus Aminopeptidase (SGAP, Leucine aminopeptidase (LAP), aminopeptidase S, Mername-AA022 peptidase) subfamily. SGAP is a di-zinc exopeptidase with high preference towards large hydrophobic amino-terminal residues, with Leu being the most efficiently cleaved. It can accommodate all except Pro and Glu residues in the P1' position. It is a monomeric (30 kDa), calcium-activated and calcium-stabilized enzyme; its activation by calcium correlates with substrate specificity and it has thermal stability only in the presence of calcium. Although SGAP contains a calcium binding site, it is not conserved in many members of this subfamily. SGAP is present in the extracellular fluid of S. griseus cultures.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241  78 KIKVDDLNATAWDLYRLAnystpDYGHPTRVIGSKGHNKTMEYILNVFDDMqDYYDVSLQEFEALsgkiisfnlsdaetg 157
Cdd:cd03876   1 DITVDNLMAHLQQLQDIA-----DANGGNRAFGSPGYNASVDYVKNELKAA-GYYDVTLQPFTSL--------------- 59

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 158 ksfanttafalsppvdgfvgklveipnlgceekdyasvvpprhnekqialiergkcpfgdksnlagkfgftavviydnep 237
Cdd:cd03876     --------------------------------------------------------------------------------

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 238 kskeglhgtlgeptkhtvatvgvpykvgkklianialnidyslyfamdsyveFIKTQNIIADTKHGDPDNIVALGAHSDS 317
Cdd:cd03876  60 ----------------------------------------------------YRTTYNVIAETKGGDPNNVVMLGAHLDS 87

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 318 VEEGPGINDDGSGTISLLNVAKQLTHFKINNKVRFAWWAAEEEGLLGSNFYAYNLTKEENSKIRVFMDYDMMASPNYEYE 397
Cdd:cd03876  88 VSAGPGINDNGSGSAALLEVALALAKFKVKNAVRFAWWTAEEFGLLGSKFYVNNLSSEERSKIRLYLNFDMIASPNYGYF 167

                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 398 IYDANNKEN----PKGSEELKNLYVDYYKAHHLNYTLVPFDGRSDYVGFINNGIPAGGIATGAEKNNV---------NNG 464
Cdd:cd03876 168 IYDGDGSAFnltgPPGSAEIERLFEAYFTSLGLPSTPTEFDGRSDYAPFIEAGIPAGGLFTGAEGIKTeeqaalwggTAG 247

                       410       420       430       440
                ....*....|....*....|....*....|....*....|..
gi 82795241 465 KVLDRCYHQLCDDVSNLSWDAFITNTKLIAHSVATYADSFEG 506
Cdd:cd03876 248 VAYDPCYHQACDTIDNINRTALLRNADAIAHAVATYARSTEG 289

PA_ScAPY_like: Protease-associated domain containing proteins like Saccharomyces cerevisiae aminopeptidase Y (ScAPY). This group contains various PA domain-containing proteins similar to the S. cerevisiae APY, including Trichophyton rubrum leucine aminopeptidase 1(LAP1). Proteins in this group belong to the peptidase M28 family. ScAPY hydrolyzes amino acid-4-methylcoumaryl-7-amides (MCAs). ScAPY more rapidly hydrolyzes dipeptidyl-MCAs. Hydrolysis of amino acid-MCAs or dipeptides is stimulated by Co2+ while the hydrolysis of dipeptidyl-MCAs, tripeptides, and longer peptides is inhibited by Co2+. ScAPY is vacuolar and is activated by proteolytic processing. LAP1 is a secreted leucine aminopeptidase. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 155 ETGKSFANTTAFALSPPVDGFvGKLVEIPNLGCEEKDYASVVpprhnEKQIALIERGKCPFGDKSNLAGKFGFTAVVIYD 234
Cdd:cd02130   3 SANGEAIPTTAFTYSPAGEVT-GPLVVVPNLGCDAADYPASV-----AGNIALIERGECPFGDKSALAGAAGAAAAIIYN 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 82795241 235 NEPksKEGLHGTLGEPTKHTVATVGVPYKVGKKLIANIALniDYSLYFAM 284
Cdd:cd02130  77 NVP--AGGLSGTLGEPSGPYVPTVGISQEDGKALVAALAN--GGEVSANL 122

M28 Zn-peptidases include aminopeptidases and carboxypeptidases; Peptidase M28 family (also called aminopeptidase Y family) contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. The aminopeptidases in this family are also called bacterial leucyl aminopeptidases, but are able to release a variety of N-terminal amino acids. IAP aminopeptidase and aminopeptidase Y preferentially release basic amino acids while glutamate carboxypeptidase II preferentially releases C-terminal glutamates. Plasma glutamate carboxypeptidase (PGCP) and glutamate carboxypeptidase II (NAALADase) hydrolyze dipeptides. Several members of the M28 peptidase family have PA domain inserts which may participate in substrate binding and/or in promoting conformational changes, which influence the stability and accessibility of the site to substrate. These include prostate-specific membrane antigen (PSMA), yeast aminopeptidase S (SGAP), human transferrin receptors (TfR1 and TfR2), plasma glutamate carboxypeptidase (PGCP) and several predicted aminopeptidases where relatively little is known about them. Also included in the M28 family are glutaminyl cyclases (QC), which are involved in N-terminal glutamine cyclization of many endocrine peptides. Nicastrin and nicalin belong to this family but lack the amino-acid conservation required for catalytically active aminopeptidases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 294 QNIIAD-TKHGDPDNIVALGAHSDSVEEGPGINDDGSGTISLLNVAKQLT--HFKINNKVRFAWWAAEEEGLLGSNFYAY 370
Cdd:cd02690   2 YNVIATiKGSDKPDEVILIGAHYDSVPLSPGANDNASGVAVLLELARVLSklQLKPKRSIRFAFWDAEELGLLGSKYYAE 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 371 NLtKEENSKIRVFMDYDMMASPNYEYEIYDA--NNKENPKGSEELKNLYVDYYKAhhLNYTLVPFDGRSDYVGFINNGIP 448
Cdd:cd02690  82 QL-LSSLKNIRAALNLDMIGGAGPDLYLQTApgNDALVEKLLRALAHELENVVYT--VVYKEDGGTGGSDHRPFLARGIP 158

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 82795241 449 AGGIATGAEKNNvnngkvldRCYHQLCDDVSNLSWDAFITNTKLIAH 495
Cdd:cd02690 159 AASLIQSESYNF--------PYYHTTQDTLENIDKDTLKRAGDILAS 197

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 294 QNIIADTKHGD-PDNIVALGAHSDSVEEG---------PGINDDGSGTISLLNVAKQLTHFKINNK-VRFAWWAAEEEGL 362
Cdd:cd03877   2 HNVVGVLEGSDlPDETIVIGAHYDHLGIGggdsgdkiyNGADDNASGVAAVLELARYFAKQKTPKRsIVFAAFTAEEKGL 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 363 LGSNFYAYNLtKEENSKIRVFMDYDMMASPNYEYEIY----DANNKENP-KGSEELKNLYVDYYKAHHLNYtlvpfdGRS 437
Cdd:cd03877  82 LGSKYFAENP-KFPLDKIVAMLNLDMIGRLGRSKDVYligsGSSELENLlKKANKAAGRVLSKDPLPEWGF------FRS 154

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 82795241 438 DYVGFINNGIPAGGIATGAEKnnvnngkvldrCYHQLCDDVSNLSWDAFITNTKLI 493
Cdd:cd03877 155 DHYPFAKAGVPALYFFTGLHD-----------DYHKPSDDYEKIDYEGMARVVNLI 199

PA: Protease-associated (PA) domain. The PA domain is an insert domain in a diverse fraction of proteases. The significance of the PA domain to many of the proteins in which it is inserted is undetermined. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate. Proteins into which the PA domain is inserted include the following: i) various signal peptide peptidases including, hSPPL2a and 2b which catalyze the intramembrane proteolysis of tumor necrosis factor alpha, ii) various proteins containing a C3H2C3 RING finger including, Arabidopsis ReMembR-H2 protein and various E3 ubiquitin ligases such as human GRAIL (gene related to anergy in lymphocytes), iii) EDEM3 (ER-degradation-enhancing mannosidase-like 3 protein), iv) various plant vacuolar sorting receptors such as Pisum sativum BP-80, v) glutamate carboxypeptidase II (GCPII), vi) yeast aminopeptidase Y, vii) Vibrio metschnikovii VapT, a sodium dodecyl sulfate (SDS) resistant extracellular alkaline serine protease, viii) lactocepin (a cell envelope-associated protease from Lactobacillus paracasei subsp. paracasei NCDO 151), ix) various subtilisin-like proteases such as melon Cucumisin, and x) human TfR (transferrin receptor) 1 and 2.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 153 DAETGKSFANTTAFALSPPVDgfVGKLVEIPNLGCEEKDYAsvVPPRHNEKQIALIERGKCPFGDKSNLAGKFGFTAVVI 232
Cdd:cd00538   1 DVILATTGYAGSALLFNPPSS--PVGVVAGPLVGCGYGTTD--DSGADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAVII 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 82795241 233 YDNEPkSKEGLHGTLG-EPTKHTVATVGVPYKVGKKLIANIALNIDYSLYF 282
Cdd:cd00538  77 YNNGD-DPGPQMGSVGlESTDPSIPTVGISYADGEALLSLLEAGKTVTVDL 126

M28 Zn-peptidase Aeromonas (Vibrio) proteolytica aminopeptidase; Peptidase family M28; Aeromonas (Vibrio) proteolytica aminopeptidase (AAP; leucine aminopeptidase from Vibrio proteolyticus; Bacterial leucyl aminopeptidase; E.C. 3.4.11.10) subfamily. AAP is a small (32kDa), heat stable leucine aminopeptidase and is active as a monomer. Similar forms of the enzyme have been isolated from Escherichia coli and Staphylococcus thermophilus. Leucine aminopeptidases, in general, play important roles in many biological processes such as protein catabolism, hormone degradation, regulation of migration and cell proliferation, as well as HIV infection and proliferation. AAP is a broad-specificity enzyme, utilizing two zinc(II) ions in its active site to remove N-terminal amino acids, with preference for large hydrophobic amino acids in the P1 position of the substrate, Leu being the most efficiently cleaved. It can accommodate all residues, except Pro, Asp and Glu in the P1' position.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 305 PDNIVALGAHSDSVEEG-------PGINDDGSGTISLLNVAKQLTH--FKINNKVRFAWWAAEEEGLLGSN--FYAYnlt 373
Cdd:cd03879  87 SDEIVVIGAHQDSINGSnpsngraPGADDDGSGTVTILEALRVLLEsgFQPKNTIEFHWYAAEEGGLLGSQaiATQY--- 163

                        90
                ....*....|....*
gi 82795241 374 KEENSKIRVFMDYDM 388
Cdd:cd03879 164 KSEGKNVKAMLQLDM 178

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 295 NIIA--DTKHGDPDNIVALGAHSDSVEEG--------------PGINDDGSGTISLLNVAKQL----THFKINNKVRFAW 354
Cdd:cd05663  57 NVIGvlPGKGDVADETVVVGAHYDHLGYGgegslargdeslihNGADDNASGVAAMLELAAKLvdsdTSLALSRNLVFIA 136

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 355 WAAEEEGLLGSNFYAYNLTKeENSKIRVFMDYDMM--------------ASPNYEYEIyDANNKENPkgseelknlyvdy 420
Cdd:cd05663 137 FSGEELGLLGSKHFVKNPPF-PIKNTVYMINMDMVgrlrdnklivqgtgTSPGWEQLV-QARNKATG------------- 201

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 82795241 421 ykahhLNYTLVPfDGR--SDYVGFINNGIPAGGIATGAEKNnvnngkvldrcYHQLCDDVSNLSWD 484
Cdd:cd05663 202 -----FKLILDP-TGYgpSDHTSFYLDDVPVLHFFTGAHSD-----------YHRPSDDSDKLNYD 250

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 293 TQNIIADTKHGD-PDNIVALGAHSDSVEEGPGINDDGSGTISLLNVAKQLTHFKINNK--VRFAWWAAEEEGLLGSNFYA 369
Cdd:cd08015   1 TYNVIAEIPGSDkKDEVVILGAHLDSWHGATGATDNGAGTAVMMEAMRILKAIGSKPKrtIRVALWGSEEQGLHGSRAYV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 370 YnltkeenskiRVFMDYDMMASPNYEYEIYDANNKENpkGSEELKNLY-------VDYYKA-----HHLNYTLVPFD--G 435
Cdd:cd08015  81 E----------KHFGDPPTMQLQRDHKKISAYFNLDN--GTGRIRGIYlqgnlaaYPIFSAwlypfHDLGATTVIERntG 148

                       170
                ....*....|....
gi 82795241 436 RSDYVGFINNGIPA 449
Cdd:cd08015 149 GTDHAAFDAVGIPA 162

PA domain; The PA (Protease associated) domain is found as an insert domain in diverse proteases. The PA domain is also found in a plant vacuolar sorting receptor Swiss:O22925 and members of the RZF family Swiss:O43567. It has been suggested that this domain forms a lid-like structure that covers the active site in active proteases, and is involved in protein recognition in vacuolar sorting receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241   177 GKLVEIPnlGCEEKDYASvvPPRHNEKQIALIERGKCPFGDKSNLAGKFGFTAVVIYDNEPKSKEGLH--GTLGEPTKHT 254
Cdd:pfam02225   2 GPLVLAP--GCYAGDGIP--ADFDVKGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGPPGagGNELYPDGIY 77

                          90
                  ....*....|....
gi 82795241   255 VATVGVPYKVGKKL 268
Cdd:pfam02225  78 IPAVGVSRADGEAL 91

PA_C-RZF_ like: Protease-associated (PA) domain C_RZF-like. This group includes various PA domain-containing proteins similar to C-RZF (chicken embryo RING zinc finger) protein. These proteins contain a C3H2C3 RING finger. C-RZF is expressed in embryo cells and is restricted mainly to brain and heart, it is localized to both the nucleus and endosomes. Additional C3H2C3 RING finger proteins belonging to this group, include Arabidopsis ReMembR-H2 protein and mouse sperizin. ReMembR-H2 is likely to be an integral membrane protein, and to traffic through the endosomal pathway. Sperizin is expressed in haploid germ cells and localized in the cytoplasm, it may participate in spermatogenesis. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 151 LSDAETGKSFANTTA-FALSPPVDGFVGKLVE-IPNLGCEEKDYASVVPPrHNEKQIALIERGKCPFGDKSNLAGKFGFT 228
Cdd:cd02123  15 LADSNLTDEFDDLPAnFGPIPPGSGLKGVLVVaEPLNACSPIENPPLNSN-ASGSFIVLIRRGNCSFETKVRNAQRAGYK 93

                ....*....
gi 82795241 229 AVVIYDNEP 237
Cdd:cd02123  94 AAIVYNDES 102

PA_C5a_like: Protease-associated domain containing proteins like Streptococcus pyogenes C5a peptidase. This group contains various PA domain-containing proteins similar to S. pyogenes C5a, including, i) Vpr, a minor extracellular serine protease from Bacillus subtilis, ii) a large molecular mass collagenolytic protease from Geobacillus collagenovorans MO-1, and iii) PrtS, a cell envelope protease from Streptococcus thermophilus CNRZ 385. Proteins in this group belong to the peptidase S8 family. C5a peptidase is a cell surface serine protease which specifically inactivates C5a [a chemotactic peptide, which attracts polymorphonuclear leukocytes (PMNs)], by cleaving it to release a 7-residue carboxy-terminal fragment which contains the PMN binding site. The significance of the PA domain to these proteins has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 205 IALIERGKCPFGDKSNLAGKFGFTAVVIYDNEPKSkegLHGTLGEptKHTVATVGVPYKVGKKLIAniALNIDYSLYFam 284
Cdd:cd02133  50 IALIQRGEITFVEKIANAKAAGAVGVIIYNNVDGL---IPGTLGE--AVFIPVVFISKEDGEALKA--ALESSKKLTF-- 120

                        90
                ....*....|....*...
gi 82795241 285 DSYVEfIKTQNIIADTKH 302
Cdd:cd02133 121 NTKKE-KATNPDLADFSS 137

PA_subtilisin_1: Protease-associated domain containing subtilisin-like proteases, subgroup 1. A subgroup of PA domain-containing subtilisin-like 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 subtilisin-like proteases: i) melon cucumisin, ii) Arabidopsis thaliana Ara12, iii) Alnus glutinosa ag12, iv) members of the tomato P69 family, and v) tomato LeSBT2. However, these proteins belong to other subtilisin-like subgroups. Relatively little is known about proteins in this subgroup.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 167 ALSPPVDGFVGKLVEIP--NLGCEEKDYASVVpprhnEKQIALIERGKCPFGDKSNLAGKFGFTAVVIYDNEPkskEGLH 244
Cdd:cd04818   8 ALTNVTADVVLAGAAPAsnTDGCTAFTNAAAF-----AGKIALIDRGTCNFTVKVLNAQNAGAIAVIVANNVA---GGAP 79

                        90       100       110
                ....*....|....*....|....*....|..
gi 82795241 245 GTLG-EPTKHTVATVGVPYKVGKKLIANIALN 275
Cdd:cd04818  80 ITMGgDDPDITIPAVMISQADGDALKAALAAG 111

M28 Zn-Peptidases; Peptidase family M28 (also called aminopeptidase Y family), uncharacterized subfamily. The M28 family contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. This subfamily is composed of uncharacterized proteins that do not contain a protease-associated (PA) domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 295 NIIADTKHGDPDNIVAL-GAHSD--SVEEG---PGINDDGSGTISLLNVAKQLTHFKINNKVRFAWWAAEEEGLLGSNFY 368
Cdd:cd05662  64 NVLAVIKGSEPPTKWRVvSAHYDhlGIRGGkiyNGADDNASGVAALLALAEYFKKHPPKHNVIFAATDAEEPGLRGSYAF 143

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 369 AYNLtKEENSKIRVFMDYDMMASPNYEyEIYDANNKENPKGSEELKNLYVDYYKAHHLNytlvPFDGR---------SDY 439
Cdd:cd05662 144 VEAL-KVPRAQIELNINLDMISRPERN-ELYVEGASQFPQLTSILENVKGTCIKALHPK----DTDGSigsidwtraSDH 217

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 440 VGFINNGIP--AGGIATGAEknnvnngkvldrcYHQLCDDVSNLSWDaFITNTKLIAHSV 497
Cdd:cd05662 218 YPFHKAKIPwlYFGVEDHPD-------------YHKPTDDFETIDQE-FFAAVVESAVQL 263

M28 Zn-peptidase Transferrin Receptor-like family; Peptidase M28 family; Transferrin Receptor (TfR) and prostate-specific membrane antigen (PSMA, also called glutamate carboxypeptidase or GCP-II) subfamily. TfR and PSMA are homodimeric type II transmembrane proteins containing three distinct domains: protease-like, apical or protease-associated (PA) and helical domains. The protease-like domain is a large extracellular portion (ectodomain). In TfR, it contains a binding site for the transferrin molecule and has 28% identity to membrane glutamate carboxypeptidase II (mGCP-II or PSMA). The PA domain is inserted between the first and second strands of the central beta sheet in the protease-like domain. TfR1 is widely expressed, and is a key player in the uptake of iron-loaded transferrin (Tf) into cells. The TfR1 homodimer binds two molecules of Tf and the complex is then internalized. TfR1 may also participate in cell growth and proliferation. TfR2 binds Tf but with a significantly lower affinity than TfR1. It is expressed chiefly in hepatocytes, hematopoietic cells, and duodenal crypt cells; its expression overlaps with that of hereditary hemochromatosis protein (HFE). TfR2 is involved in iron homeostasis; in humans, mutations in TfR2 are associated with a form of hemochromatosis (HFE3). PSMA is over-expressed predominantly in prostate cancer (PCa) as well as in the neovasculature of most solid tumors, but not in the vasculature of normal tissues. PSMA is considered a biomarker for PCa and possibly for use as an imaging and therapeutic target. The extracellular domain of PSMA possesses two unique enzymatic functions: N-acetylated, alpha-linked acidic dipeptidase (NAALADase) which cleaves terminal glutamate from the neurodipeptide N-acetyl-aspartyl-glutamate (NAAG), and folate hydrolase (FOLH) which cleaves the terminal glutamates from gamma-linked polyglutamates (carboxypeptidase). A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants. While related in sequence to peptidase M28 GCP-II, TfR lacks the metal ion coordination centers and protease activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 287 YVEFIKTQNIIADTK-HGDPDNIVALGAHSDSVeeGPGINDDGSGTISLLNVAK--QLTHFKINNK----VRFAWWAAEE 359
Cdd:cd03874  51 LEEYSPITNVVGKIEgIEQPDRAIIIGAHRDSW--GYGAGYPNSGTAVLLEIARlfQQLKKKFGWKplrtIYFISWDGSE 128

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 360 EGLLGSNFYAYNLTKEENSKIRVFMDYDMMASPNYEYEI----------YDANNKENPKGSEELKNlyvdyykaHHLNYT 429
Cdd:cd03874 129 FGLAGSTELGEDRKASLKDEVYAYINIDQLVIGNSELDVdahpllqslfRKASKKVKFPGNEDWWK--------HSPNAK 200

                       170       180
                ....*....|....*....|.
gi 82795241 430 LVPFDGRSDYVGFIN-NGIPA 449
Cdd:cd03874 201 VSNLHQYGDWTPFLNhLGIPV 221

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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 295 NIIADTKHGDPDNIVALGAHSDSVEEGPGIN---------------------DDGSGTISLLNVAKQL--THFKINNKVR 351
Cdd:cd03873   1 NLIARLGGGEGGKSVALGAHLDVVPAGEGDNrdppfaedteeegrlygrgalDDKGGVAAALEALKRLkeNGFKPKGTIV 80

                        90       100
                ....*....|....*....|....*....
gi 82795241 352 FAWWAAEEEGLLGSNFYAYNLTKEENSKI 380
Cdd:cd03873  81 VAFTADEEVGSGGGKGLLSKFLLAEDLKV 109

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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 82795241 295 NIIADTKHGDPDNIVALGAHSDSV----EEGPGINDDGSGTISLLNVAKQLTH----FKINNKVRFAWWAAEEEGLLGSN 366
Cdd:cd03881 199 PINTSWEVKTSKKIVLVAARMDSTsffrDVAPGADSSLSGFVALLAAAEALKKvdgkGSLKRNVVFAFFNGESWGYIGSS 278

                ....*...
gi 82795241 367 FYAYNLTK 374
Cdd:cd03881 279 RFVYDMEN 286

M28 Zn-peptidase glutaminyl cyclase; Peptidase M28 family, glutaminyl cyclase (QC; EC 2.3.2.5) subfamily. QC is involved in N-terminal glutamine cyclization of many endocrine peptides and is typically abundant in brain tissue. N-terminal glutamine residue cyclization is an important post-translational event in the processing of numerous bioactive proteins, including neuropeptides, hormones, and cytokines during their maturation in the secretory pathway. The N-terminal pGlu protects them from exopeptidase degradation and/or enables them to have proper conformation for binding to their receptors. QCs are highly conserved from yeast to human. In humans, several genetic diseases, such as osteoporosis, appear to result from mutations of the QC gene. N-terminal glutamate cyclization into pyroglutamate (pGlu) is a reaction that may be related to the formation of several plaque-forming peptides, such as amyloid-(A) peptides and collagen-like Alzheimer amyloid plaque component, which play a pivotal role in Alzheimer's disease.

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 82795241 106 TRVIGSKGHNKTMEYILNVFDDMQDYYDVSLQEFEA 141
Cdd:cd03880  26 PRVPGSPGHREVRNFIIDFLKSLLAGWTVELDNFTE 61

PA_PoS1_like: Protease-associated (PA) domain PoS1-like. This group includes various PA domain-containing proteins similar to Pleurotus ostreatus (Po)S1. PoSl, the main extracellular protease in P. ostreatus is a subtilisin-like serine protease belonging to the peptidase S8 family. Ca2+ and Mn2+ both stimulate the protease activity of (Po)S1. Ca2+ protects PoS1 from autolysis. PoS1 is a monomeric glycoprotein, which may play a role in the regulation of laccases in lignin formation. (Po)S1 participates in the degradation of POXA1b, and in the activation of POXA3, (POXA1b and POXA3 are laccase isoenzymes), but its effect may be indirect. The significance of the PA domain to PoS1 has not been ascertained. It may be a protein-protein interaction domain. At peptidase active sites, the PA domain may participate in substrate binding and/or promoting conformational changes, which influence the stability and accessibility of the site to substrate.

                        10        20        30
                ....*....|....*....|....*....|....*
gi 82795241 203 KQIALIERGKCPFGDKSNLAGKFGFTAVVIYDNEP 237
Cdd:cd02124  56 GYIVLVRRGTCTFATKAANAAAKGAKYVLIYNNGS 90