PA_hSPPL_like: Protease-associated domain containing human signal peptide peptidase-like (hSPPL)-like. This group contains various PA domain-containing proteins similar to hSPPL2a and 2b. These SPPLs are GxGD aspartic proteases. SPPL2a is sorted to the late endosomes, SPPL2b to the plasma membrane. In activated dendritic cells, hSPPL2a and 2b catalyze the intramembrane proteolysis of tumor necrosis factor alpha triggering IL-12 production. hSPPL2a and 2b may have a broad substrate spectrum. The significance of the PA domain to these SPPLs 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 612012205  38 YCILYNSQWAHLPPGLGKASLLQLQDQTTSVLCSQSDVPSGGFNNRIPMVMRGNCTFYEKVKLAQMNGARGLLVVSREKL 117
Cdd:cd02129    1 YCILYNSQWASLPSDLDKATLLPLRNLTSSVLCSASDVPPGGLKGKAVVVMRGNCTFYEKARLAQSLGAEGLLIVSRERL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 612012205 118 VPPGGNKTQYDEIGIPVALLSYKDMLDICKTFGHSVRVAL 157
Cdd:cd02129   81 VPPSGNRSEYEKIDIPVALLSYKDMLDIQQTFGDSVKVAM 120

Presenilin, signal peptide peptidase, family; Presenilin 1 and presenilin 2 are polytopic membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. Distant homologues, present in eukaryotes and archaea, also contain conserved aspartic acid residues which are predicted to contribute to catalysis. At least one member of this family has been shown to possess signal peptide peptidase activity.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612012205   211 ETVDVTPIMIGVFVVMCCSMLVLLYYFYDHLVYMIITIFCLASSTSLYSCLYPCIKRLPFgkcrvpdnnlpyfhkrpqIR 290
Cdd:smart00730   1 EYSLLNSLVAIVFPIVATFVLVLLYKFFKYLVIVLVIYFSSLGVLFLYSLLYPLEVFRVD------------------YP 62

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612012205   291 MLLLAIFCITVSIIWGVFRNedqWAWVLQDALGIAFCLYMLKTIRLPTFKACTLLLLVLFIYDVFFVFITPFltksGNSI 370
Cdd:smart00730  63 TLLILLLNFAVVGFWCIHRK---GAWIQQDLIGISLCMAILFILRLPSEWTAWILLGALFIYDIFAVFGTPG----PLRV 135

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612012205   371 MVEVAAGPSDSTthEKLPMVLKVPRLNSSPLALCDRPFSLLGFGDILVPGLLVAYCHRFDIQVQSSRVYFVACTIAYGIG 450
Cdd:smart00730 136 MVEVATGRDEPI--KVFPALLYVPRLVVSFEDDEEERFSMLGLGDIVFPGILVASAARFDVSVRSDSNYFLACFVAYGIG 213

                          250       260       270
                   ....*....|....*....|....*....|....*.
gi 612012205   451 LLITFVALAWMQRGQPALLYLVPCTVITSFVIALWR 486
Cdd:smart00730 214 LILTLVLLALFKKAQPALPYLVPFTLVFYLLTALLR 249

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 612012205   70 CSQSDVPSGGFN--NRIPMVMRGNCTFYEKVKLAQMNGARGLLVVSREKLVPP----GGNKTQYDEIGIPVALLSYKDML 143
Cdd:pfam02225  10 CYAGDGIPADFDvkGKIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGGppgaGGNELYPDGIYIPAVGVSRADGE 89

                  ..
gi 612012205  144 DI 145
Cdd:pfam02225  90 AL 91

Presenilin, signal peptide peptidase, family; Presenilin 1 and presenilin 2 are polytopic membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. Distant homologues, present in eukaryotes and archaea, also contain conserved aspartic acid residues which are predicted to contribute to catalysis. At least one member of this family has been shown to possess signal peptide peptidase activity.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612012205   211 ETVDVTPIMIGVFVVMCCSMLVLLYYFYDHLVYMIITIFCLASSTSLYSCLYPCIKRLPFgkcrvpdnnlpyfhkrpqIR 290
Cdd:smart00730   1 EYSLLNSLVAIVFPIVATFVLVLLYKFFKYLVIVLVIYFSSLGVLFLYSLLYPLEVFRVD------------------YP 62

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612012205   291 MLLLAIFCITVSIIWGVFRNedqWAWVLQDALGIAFCLYMLKTIRLPTFKACTLLLLVLFIYDVFFVFITPFltksGNSI 370
Cdd:smart00730  63 TLLILLLNFAVVGFWCIHRK---GAWIQQDLIGISLCMAILFILRLPSEWTAWILLGALFIYDIFAVFGTPG----PLRV 135

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612012205   371 MVEVAAGPSDSTthEKLPMVLKVPRLNSSPLALCDRPFSLLGFGDILVPGLLVAYCHRFDIQVQSSRVYFVACTIAYGIG 450
Cdd:smart00730 136 MVEVATGRDEPI--KVFPALLYVPRLVVSFEDDEEERFSMLGLGDIVFPGILVASAARFDVSVRSDSNYFLACFVAYGIG 213

                          250       260       270
                   ....*....|....*....|....*....|....*.
gi 612012205   451 LLITFVALAWMQRGQPALLYLVPCTVITSFVIALWR 486
Cdd:smart00730 214 LILTLVLLALFKKAQPALPYLVPFTLVFYLLTALLR 249

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 612012205  74 DVPSGGFNNRIPMVMRGNCTFYEKVKLAQMNGARGLLVVSREK--LVPPGGNKTQYDEIGIPVALLSYKDMLDICKTFGH 151
Cdd:cd00538   39 DDSGADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAVIIYNNGDdpGPQMGSVGLESTDPSIPTVGISYADGEALLSLLEA 118

                 ....*...
gi 612012205 152 SVRVALYA 159
Cdd:cd00538  119 GKTVTVDL 126

PA_GO-like: Protease-associated domain containing proteins like Arabidopsis thaliana growth-on protein GRO10. This group contains various PA domain-containing proteins similar to the functionally uncharacterized Arabidopsis GRO10. The PA domain 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 612012205  70 CSQSDVPsggFNNRIPMVMRGNCTFYEKVKLAQMNGARGLLVVS-REKLVPPGGNKTQYD-EIGIPVALLS 138
Cdd:cd02132   51 CSPSTSK---LSGSIALVERGECAFTEKAKIAEAGGASALLIINdQEELYKMVCEDNDTSlNISIPVVMIP 118

PA _GRAIL_like: Protease-associated (PA) domain GRAIL-like. This group includes PA domain containing E3 (ubiquitin ligases) similar to human GRAIL (gene related to anergy in lymphocytes) protein. Proteins in this group contain a C3H2C3 RING finger. E3 ubiquitin ligase is part of an enzymic cascade, the end result of which is the ubiquitination of proteins. In this cascade, E1 activates the ubiquitin, the activated ubiquitin is carried by E2, and E3 recognizes the acceptor protein as well as catalyzes the transfer of the activated ubiquitin from E2 to this acceptor. GRAIL, a transmembrane protein localized in the endosomes, controls the development of T cell clonal anergy, and may ubiquitinate membrane-associated targets for T cell activation. GRAIL1 is associated with, and regulated by, two isoforms of otubain 1 (the ubiquitin-specific protease). Additional E3s belonging to this group include human (h)Goliath and Xenopus GREUL1 (Goliath Related E3 Ubiquitin Ligase 1). hGoliath and GRAIL both have the property of self-ubiquitination. hGoliath is expressed in leukocytes; its expression and localization is not modified in leukemia. GREUL1 may play a role in the generation of anterior ectoderm. 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
                 ....*....|....*....|....*....|....*....|..
gi 612012205  84 IPMVMRGNCTFYEKVKLAQMNGARGLLVVSreklVPPGGNKT 125
Cdd:cd02122   63 IALIQRGNCTFEEKIKLAAERNASAVVIYN----NPGTGNET 100

PA_1: Protease-associated (PA) domain subgroup 1. A subgroup of PA-domain containing proteins. Proteins in this subgroup contain a RING-finger (Really Interesting New Gene) domain C-terminal to this 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 in this group contain a C-terminal RING-finger domain. Proteins into which the PA domain is inserted include the following: i) various signal peptide peptidases: such as hSPPL2a and 2b, ii) various E3 ubiquitin ligases similar to human GRAIL (gene related to anergy in lymphocytes) protein, iii) various proteins containing a RING finger motif such as Arabidopsis ReMembR-H2 protein, iv) EDEM3 (ER-degradation-enhancing mannosidase-like 3 protein), v) various plant vacuolar sorting receptors such as Pisum sativum BP-80, vi) prostate-specific membrane antigen (PSMA), vii) yeast aminopeptidase Y viii) Vibrio metschnikovii VapT, a sodium dodecyl sulfate (SDS) resistant extracellular alkaline serine protease, ix) various subtilisin-like proteases such as Cucumisin from the juice of melon fruits, and x) human TfR (transferrin receptor) 1 and human TfR2. The proteins listed above belong to other subgroups; relatively little is known about proteins in this subgroup.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 612012205  72 QSDVPSGGFNNRIPMVMRGNCTFYEKVKLAQMNGARGLLVVSREklvPPGGNKTQY-----DEIGIPVALLSYKD 141
Cdd:cd04813   30 CSLQEHAEIDGKVALVLRGGCGFLDKVMWAQRRGAKAVIVGDDE---PGRGLITMFsngdtDNVTIPAMFTSRTS 101

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 612012205  89 RGNCTFYEKVKLAQMNGARGLLVVSREK--LVPPGGNKTQYDEIGIPVALLSYKDMLDICKTFGHSVRVAL 157
Cdd:cd02123   75 RGNCSFETKVRNAQRAGYKAAIVYNDESndLISMSGNDQEIKGIDIPSVFVGKSTGEILKKYASYEKGVIL 145

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 612012205  70 CSQSDVPSGGFNNrIPMVMRGNCTFYEKVKLAQMNGARGLLVVSREKLVPPGGNKTQYDEIGIPVALLSYKD 141
Cdd:cd02130   34 CDAADYPASVAGN-IALIERGECPFGDKSALAGAAGAAAAIIYNNVPAGGLSGTLGEPSGPYVPTVGISQED 104