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 6755338   23 LFAFLNLLPveADILAYNFENASQTFEDLPARFGYRLPAEGLKGFLINSKPENACEPIVPPPLKDNSSGTFIVLIRRLDC 102
Cdd:cd02123   1 LLVVSPLAT--ADKLALADSNLTDEFDDLPANFGPIPPGSGLKGVLVVAEPLNACSPIENPPLNSNASGSFIVLIRRGNC 78

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 6755338  103 NFDIKVLNAQRAGYKAAIVHNVDSDDLISMGSNDiDTLKKIDIPSVFIGESSANSLKDEFTYEKGghIILVPELSLPL 180
Cdd:cd02123  79 SFETKVRNAQRAGYKAAIVYNDESNDLISMSGND-QEIKGIDIPSVFVGKSTGEILKKYASYEKG--VILIPDLPLKI 153

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 6755338   23 LFAFLNLLPveADILAYNFENASQTFEDLPARFGYRLPAEGLKGFLINSKPENACEPIVPPPLKDNSSGTFIVLIRRLDC 102
Cdd:cd02123   1 LLVVSPLAT--ADKLALADSNLTDEFDDLPANFGPIPPGSGLKGVLVVAEPLNACSPIENPPLNSNASGSFIVLIRRGNC 78

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 6755338  103 NFDIKVLNAQRAGYKAAIVHNVDSDDLISMGSNDiDTLKKIDIPSVFIGESSANSLKDEFTYEKGghIILVPELSLPL 180
Cdd:cd02123  79 SFETKVRNAQRAGYKAAIVYNDESNDLISMSGND-QEIKGIDIPSVFVGKSTGEILKKYASYEKG--VILIPDLPLKI 153

RING finger, H2 subclass, found in RING finger protein 13 (RNF13) and similar proteins; RNF13 is a widely expressed membrane-associated E3 ubiquitin-protein ligase that is functionally significant in the regulation of cancer development, muscle cell growth, and neuronal development. Its expression is developmentally regulated during myogenesis and is upregulated in various tumors. RNF13 negatively regulates cell proliferation through its E3 ligase activity. It functions as an important regulator of inositol-requiring transmembrane kinase/endonuclease IRE1alpha, mediating endoplasmic reticulum (ER) stress-induced apoptosis through the activation of the IRE1alpha-TRAF2-JNK signaling pathway. Moreover, RNF13 is involved in the regulation of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex via the ubiquitination of snapin, a SNAP25-interacting protein, which thereby controls synaptic function. In addition, RNF13 participates in regulating the function of satellite cells by modulating cytokine composition. RNF13 is evolutionarily conserved among many metazoans and contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                        10        20        30
                ....*....|....*....|....*....|..
gi 6755338  230 KFKKGDEYDVCAICLEEYEDGDKLRILPCSHG 261
Cdd:cd16796   1 KFKKGDEYDVCAICLDEYEEGDKLRILPCSHA 32

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 6755338     79 PIVPPPLKDNSSGTF--------IVLIRRLDCNFDIKVLNAQRAGYKAAIVHNVDSDDL-ISMGSNDIDTLKKIDIPSVF 149
Cdd:pfam02225   3 PLVLAPGCYAGDGIPadfdvkgkIVLVRCTFGFRAEKVRNAQAAGAAGVIIYNNVEGLGgPPGAGGNELYPDGIYIPAVG 82

                  ....*....
gi 6755338    150 IGESSANSL 158
Cdd:pfam02225  83 VSRADGEAL 91

RING-finger-containing ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338   35 DILAYNFENASQTFEDLPARfgyrlpAEGLKGFLINSKPENACEPIVPPPLKDNSSGTFIvLIRRLDCNFDIKVLNAQRA 114
Cdd:COG5540  97 DLISGYFGDGDDGREYDETR------IPPPSRDLRGSGRKVRGSARQEVPSVEERNLVDR-CNRRGNETEEDPTRERRRT 169

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338  115 GYKAAIV---HNVDSDDLISMGSNDIDTLKKIDIPSVFIGESSANSLKDEFTYEKG------------------------ 167
Cdd:COG5540 170 RFKGVIRgseRNGETFRLHYMVAPDKVDPRSEGVEDPVTLTTSINVTWDGLGNTYQapsqsaeaqdetgdmfwprlsrfv 249

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338  168 -GHIILVPELSLPLEYYL---------IPFLIIVGICLILIVIFmitkFVQDRHRNRRNRlrKDQLKKLPVHKFKKGDEY 237
Cdd:COG5540 250 gSRGFRVVFPRIPSQELRflfltqskgSRFNIILEIQINFDVGF----YSSSEAIPTTTT--KGSLKPLSIERAVEADKG 323

                       250       260
                ....*....|....*....|...
gi 6755338  238 DVCAICLEEYEDGDKLRILPCSH 260
Cdd:COG5540 324 VECAICMSNFIKNDRLRVLPCDH 346

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 6755338   23 LFAFLNLLPveADILAYNFENASQTFEDLPARFGYRLPAEGLKGFLINSKPENACEPIVPPPLKDNSSGTFIVLIRRLDC 102
Cdd:cd02123   1 LLVVSPLAT--ADKLALADSNLTDEFDDLPANFGPIPPGSGLKGVLVVAEPLNACSPIENPPLNSNASGSFIVLIRRGNC 78

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 6755338  103 NFDIKVLNAQRAGYKAAIVHNVDSDDLISMGSNDiDTLKKIDIPSVFIGESSANSLKDEFTYEKGghIILVPELSLPL 180
Cdd:cd02123  79 SFETKVRNAQRAGYKAAIVYNDESNDLISMSGND-QEIKGIDIPSVFVGKSTGEILKKYASYEKG--VILIPDLPLKI 153

T9SS-dependent M36 family metallopeptidase; Members of this family have an M36 family metallopeptidase domain, like fungalysin (see PF02128), and a C-terminal T9SS type A sorting domain (see TIGR04131).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338    31 PVEADILAYNF-ENASQTFEDLPARFGYRLPAEGLKGFLI-----NSKPENACEPIVPP-PLKDNssgtfIVLIRRLDCN 103
Cdd:NF038113 406 APDGNLLQVNApGSLAGRYPGVRAGFGPRLPDAPITGDLAlatdsSPDPNDGCDPILNAaALAGK-----IAVIRRGSCE 480

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 6755338   104 FDIKVLNAQRAGYKAAIVHNVDSDDLISMGSNDIDTlkKIDIPSVFIGESSANSLKDE 161
Cdd:NF038113 481 FAVKVLNAQNAGAIAVIIVNNVPGEPIVMGGGDTGP--PITIPSIMISQADGEAIITA 536

RING finger, H2 subclass, found in RING finger protein 13 (RNF13) and similar proteins; RNF13 is a widely expressed membrane-associated E3 ubiquitin-protein ligase that is functionally significant in the regulation of cancer development, muscle cell growth, and neuronal development. Its expression is developmentally regulated during myogenesis and is upregulated in various tumors. RNF13 negatively regulates cell proliferation through its E3 ligase activity. It functions as an important regulator of inositol-requiring transmembrane kinase/endonuclease IRE1alpha, mediating endoplasmic reticulum (ER) stress-induced apoptosis through the activation of the IRE1alpha-TRAF2-JNK signaling pathway. Moreover, RNF13 is involved in the regulation of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex via the ubiquitination of snapin, a SNAP25-interacting protein, which thereby controls synaptic function. In addition, RNF13 participates in regulating the function of satellite cells by modulating cytokine composition. RNF13 is evolutionarily conserved among many metazoans and contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                        10        20        30
                ....*....|....*....|....*....|..
gi 6755338  230 KFKKGDEYDVCAICLEEYEDGDKLRILPCSHG 261
Cdd:cd16796   1 KFKKGDEYDVCAICLDEYEEGDKLRILPCSHA 32

RING finger, H2 subclass, found in RING finger protein 167 (RNF167) and similar proteins; RNF167, also known as RING105, is an endosomal/lysosomal E3 ubiquitin-protein ligase involved in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) ubiquitination. It ubiquitinates AMPA-type glutamate receptor subunit GluA2 and regulates its surface expression, and thus acts as a selective regulator of AMPAR-mediated neurotransmission. It acts as an endosomal membrane protein which ubiquitylates vesicle-associated membrane protein 3 (VAMP3) and regulates endosomal trafficking. Moreover, RNF167 plays a role in the regulation of TSSC5 (tumor-suppressing subchromosomal transferable fragment cDNA, also known as ORCTL2/IMPT1/BWR1A/SLC22A1L), which can function in concert with the ubiquitin-conjugating enzyme UbcH6. RNF167 is widely conserved in metazoans and contains an N-terminal signal peptide, a protease-associated (PA) domain, two transmembrane domains (TM1 and TM2), and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                        10        20        30
                ....*....|....*....|....*....|
gi 6755338  238 DVCAICLEEYEDGDKLRILPCSHGMSTHTV 267
Cdd:cd16797   1 DVCAICLDEYEEGDKLRVLPCSHAYHSKCV 30

RING finger, H2 subclass, found in RING finger protein 13 (RNF13), RING finger protein 167 (RNF167), and similar proteins; This subfamily includes RING finger protein 13 (RNF13), RING finger protein 167 (RNF167), Zinc/RING finger protein 4 (ZNRF4), and similar proteins, which belong to a larger PA-TM-RING ubiquitin ligase family that has been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane domain (TM), and a C-terminal C3H2C3-type RING-H2 finger followed by a putative PEST sequence. RNF13 is a widely expressed membrane-associated E3 ubiquitin-protein ligase that functions in the regulation of cancer development, muscle cell growth, and neuronal development. Its expression is developmentally regulated during myogenesis and is upregulated in various tumors. RNF13 negatively regulates cell proliferation through its E3 ligase activity. RNF167, also known as RING105, is an endosomal/lysosomal E3 ubiquitin-protein ligase involved in the ubiquitination of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). It acts as an endosomal membrane protein which ubiquitylates vesicle-associated membrane protein 3 (VAMP3) and regulates endosomal trafficking. Moreover, RNF167 plays a role in the regulation of TSSC5 (tumor-suppressing subchromosomal transferable fragment cDNA, also known as ORCTL2/IMPT1/BWR1A/SLC22A1L), which can function in concert with the ubiquitin-conjugating enzyme UbcH6. ZNRF4, also known as RING finger protein 204 (RNF204), or Nixin, is an endoplasmic reticulum (ER) membrane-anchored ubiquitin ligase that physically interacts with the ER-localized chaperone calnexin in a glycosylation-independent manner, inducing calnexin ubiquitination, and p97-dependent degradation. The murine protein sperizin (spermatid-specific ring zinc finger) is a homolog of human ZNRF4. It is specifically expressed in Haploid germ cells and is involved in spermatogenesis.

                        10        20        30
                ....*....|....*....|....*....|
gi 6755338  238 DVCAICLEEYEDGDKLRILPCSHGMSTHTV 267
Cdd:cd16665   1 DVCAICLDDYEEGDKLRILPCSHAYHCKCI 30

PA_VSR: Protease-associated (PA) domain-containing plant vacuolar sorting receptor (VSR). This group includes various PA domain-containing VSRs such as garden pea BP-80, pumpkin PV72, and various Arabidopsis VSRs including AtVSR1. In contrast to most eukaryotes, which only have one or two VSRs, plants have several. This may in part be a reflection of having a more complex vacuolar system with both lytic vacuoles and storage vacuoles. The lytic vacuole is thought to be equivalent to the mammalian lysosome and the yeast vacuole. Pea BP-80 is a type 1 transmembrane protein, involved in the targeting of proteins to the lytic vacuole; it has been suggested that this protein also mediates targeting to the storage vacuole. PV72 and AtVSR1 may mediate transport of seed storage proteins to protein storage vacuoles. The significance of the PA domain to VSRs 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 6755338   94 IVLIRRLDCNFDIKVLNAQRAGYKAAIVhnVDSDD--LISMG----SNDIDTLKKIDIPSVFIGESSANSLKDEF 162
Cdd:cd02125  45 ILLLDRGGCFFTLKAWNAQQAGAAAVLV--ADNVDepLLTMDtpeeSGSADYIEKITIPSALITKAFGEKLKKAI 117

RING finger, H2 subclass, found in the PA-TM-RING ubiquitin ligase family; The PA-TM-RING family represents a group of transmembrane-type E3 ubiquitin ligases, which has been characterized by an N-terminal transient signal peptide, a PA (protease-associated) domain, a TM (transmembrane) domain, as well as a C-terminal C3H2C3-type RING-H2 finger domain. It includes RNF13, RNF167, ZNRF4 (zinc and RING finger 4), GRAIL (gene related to anergy in lymphocytes)/RNF128, RNF130, RNF133, RNF148, RNF149 and RNF150 (which are more closely related), as well as RNF43 and ZNRF3, which have substantially longer C-terminal tail extensions compared with the others. PA-TM-RING proteins are expressed at low levels in all mammalian tissues and species, but they are not present in yeast. They play a common regulatory role in intracellular trafficking/sorting, suggesting that abrogation of their function may result in dysregulation of cellular signaling events in cancer.

                        10        20
                ....*....|....*....|...
gi 6755338  239 VCAICLEEYEDGDKLRILPCSHG 261
Cdd:cd16454   1 TCAICLEEFKEGEKVRVLPCNHL 23

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338   73 PENACEPIVPPPLKDNssgtfIVLIRRLDCNFDIKVLNAQRAGYKAAIV-HNVDSDDLISMGSNDIDTLkkIDIPSVFIG 151
Cdd:cd04813  26 PTDACSLQEHAEIDGK-----VALVLRGGCGFLDKVMWAQRRGAKAVIVgDDEPGRGLITMFSNGDTDN--VTIPAMFTS 98

                        90
                ....*....|
gi 6755338  152 ESSANSLKDE 161
Cdd:cd04813  99 RTSYHLLSSL 108

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        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338   53 ARFGYRLPAEGLKGFLINSKPEN---ACEP----IVPPPlkdnsSGTFIVLIRRLDCNFDIKVLNAQRAGYKAAIVHNVD 125
Cdd:cd02122  20 GRYGEHSPKEEAKGLVVVPDPPNdhyGCDPdtrfPIPPN-----GEPWIALIQRGNCTFEEKIKLAAERNASAVVIYNNP 94

                        90       100       110
                ....*....|....*....|....*....|
gi 6755338  126 SDD--LISMGSNDidtlkKIDIPSVFIGES 153
Cdd:cd02122  95 GTGneTVKMSHPG-----TGDIVAIMITNP 119

PA_EDEM3_like: protease associated domain (PA) domain-containing EDEM3-like proteins. This group contains various PA domain-containing proteins similar to mouse EDEM3 (ER-degradation-enhancing mannosidase-like 3 protein). EDEM3 contains a region, similar to Class I alpha-mannosidases (gylcosyl hydrolase family 47), N-terminal to the PA domain. EDEM3 accelerates glycoprotein ERAD (ER-associated degradation). In transfected mammalian cells, overexpression of EDEM3 enhances the mannose trimming from the N-glycans, of a model misfolded protein [alpha1-antitrypsin null (Hong Kong)] as well as, from total glycoproteins. Mannose trimming appears to be involved in the selection of ERAD substrates. EDEM3 has a different specificity of trimming than ER alpha-mannosidase 1. The significance of the PA domain to EDEM3 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 6755338   52 PARFGYRLPA-EGLKGFLINSKPENACEPIVPPplkDNSSGTfIVLIRRLDCNFDIKVLNAQRAGYKAAIV------HNV 124
Cdd:cd02126   4 PAQFGMDLTGdKAGVGRVVKAKPYRACSEITNA---EEVKGK-IAIMERGDCMFVEKARRVQKAGAIGGIVidnnegSSS 79

                        90       100
                ....*....|....*....|....*.
gi 6755338  125 DSDDLISMgSNDIDTLKKIDIPSVFI 150
Cdd:cd02126  80 DTAPMFAM-SGDGDSTDDVTIPVVFL 104

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 6755338   94 IVLIRRLDCNFDIKVLNAQRAGYKAAIVHNvDSDDLISMGSNDidtlkKIDIPSVFI----GESSANSLKDE 161
Cdd:cd02133  50 IALIQRGEITFVEKIANAKAAGAVGVIIYN-NVDGLIPGTLGE-----AVFIPVVFIskedGEALKAALESS 115

PA_hPAP21_like: Protease-associated domain containing proteins like the human secreted glycoprotein hPAP21 (human protease-associated domain-containing protein, 21kDa). This group contains various PA domain-containing proteins similar to hPAP21. Complex N-glycosylation may be required for the secretion of hPAP21. The significance of the PA domain to hPAP21 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 6755338   68 LINSKPENACEPIVPPP-LKDNssgtfIVLIRRLDCNFDIKVLNAQRAGYKAAIVHNVDSDD---LISMgSNDiDTLKKI 143
Cdd:cd02127  15 LVPADPLEACEELRNIHdINGN-----IALIERGGCSFLTKAINAQKAGALAVIITDVNNDSdeyYVEM-IQD-DSSRRA 87

                ....*..
gi 6755338  144 DIPSVFI 150
Cdd:cd02127  88 DIPAAFL 94

RING finger, H2 subclass, found in RING finger protein 43 (RNF43) and similar proteins; RNF43 is a transmembrane E3 ubiquitin-protein ligase that plays an important role in frizzled (FZD)-dependent regulation of the Wnt/beta-catenin pathway. It functions as a tumor suppressor that inhibits Wnt/beta-catenin signaling by ubiquitinating FZD receptor and targeting it to the lysosomal pathway for degradation. miR-550a-5p directly targeted the 3'-UTR of gene RNF43 and regulated its expression. Moreover, RNF43 interacts with NEDD-4-like ubiquitin-protein ligase-1 (NEDL1) and regulates p53-mediated transcription. It may also be involved in cell growth control through the interaction with HAP95, a chromatin-associated protein interfacing the nuclear envelope. Mutations of RNF43 have been identified in various tumors, including colorectal cancer (CRC), endometrial cancer, mucinous ovarian tumors, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, liver fluke-associated cholangiocarcinoma, hepatocellular carcinoma, and glioma. RNF43 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger followed by a long C-terminal region.

                        10        20
                ....*....|....*....|....*....
gi 6755338  239 VCAICLEEYEDGDKLRILPCSHGMSTHTV 267
Cdd:cd16798   5 VCAICLEEFSEGQELRIISCSHEFHRECV 33

RING finger, H2 subclass, found in RING finger proteins RNF24, RNF122, and similar proteins; This subfamily includes RNF24, RNF122, and similar proteins. RNF24 is an intrinsic membrane protein localized in the Golgi apparatus. It specifically interacts with the ankyrin-repeats domains (ARDs) of TRPC1, -3, -4, -5, -6, and -7, and affects TRPC intracellular trafficking without affecting their activity. RNF122 is a RING finger protein associated with HEK 293T cell viability. It is localized to the endoplasmic reticulum (ER) and the Golgi apparatus, and overexpressed in anaplastic thyroid cancer cells. RNF122 functions as an E3 ubiquitin ligase that can ubiquitinate itself and undergo degradation through its RING finger in a proteasome-dependent manner. Both RNF24 and RNF122 contain an N-terminal transmembrane domain and a C-terminal C3H2C3-type RING-H2 finger.

                        10        20
                ....*....|....*....|....
gi 6755338  238 DVCAICLEEYEDGDKLRILPCSHG 261
Cdd:cd16469   1 DTCAVCLEEFKLKEELGVCPCGHA 24

RING finger, H2 subclass, found in RING finger protein 12 (RNF12) and similar proteins; RNF12, also known as LIM domain-interacting RING finger protein or RING finger LIM domain-binding protein (R-LIM), is an E3 ubiquitin-protein ligase encoded by gene RLIM that is crucial for normal embryonic development in some species and for normal X inactivation in mice. It thus functions as a major sex-specific epigenetic regulator of female mouse nurturing tissues. RNF12 is widely expressed during embryogenesis, and mainly localizes to the cell nucleus, where it regulates the levels of many proteins, including CLIM, LMO, HDAC2, TRF1, SMAD7, and REX1, by proteasomal degradation. Its functional activity is regulated by phosphorylation-dependent nucleocytoplasmic shuttling. It is negatively regulated by pluripotency factors in embryonic stem cells. p53 represses its transcription through Sp1. RNF12 is the primary factor responsible for X chromosome inactivation (XCI) in female placental mammals. It is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI. It also targets REX1, an inhibitor of XCI, for proteasomal degradation. RNF12 also acts as a co-regulator for a range of transcription factors, particularly those containing a LIM homeodomain, and modulates the formation of transcriptional multiprotein complexes. It is a negative regulator of Smad7, which in turn negatively regulates the signaling of type I receptors from the transforming growth factor beta (TGF-beta) superfamily. In addition, paternal RNF12 is a critical survival factor for milk-producing alveolar cells. RNF12 contains an nuclear localization signal (NLS) and a C3H2C3-type RING-H2 finger.

                        10        20
                ....*....|....*....|....*...
gi 6755338  240 CAICLEEYEDGDKLRILPCSHGMSTHTV 267
Cdd:cd16674   3 CSVCITEYTEGNKLRKLPCSHEYHVHCI 30

RING finger, H2 subclass, found in zinc/RING finger protein 3 (ZNRF3) and similar proteins; ZNRF3, also known as RING finger protein 203 (RNF203), is a homolog of Ring finger protein 43 (RNF43). It is a transmembrane E3 ubiquitin-protein ligase that is associated with the Wnt receptor complex, and negatively regulates Wnt signaling by promoting the turnover of frizzled and lipoprotein receptor-related protein LRP6 in an R-spondin-sensitive manner. It inhibits gastric cancer cell growth and promotes cell apoptosis by affecting the Wnt/beta-catenin/TCF signaling pathway. ZNRF3 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger followed by a long C-terminal region.

                        10        20
                ....*....|....*....|.
gi 6755338  240 CAICLEEYEDGDKLRILPCSH 260
Cdd:cd16799   2 CAICLEKYIDGEELRVIPCTH 22

Ring finger domain;

                          10        20
                  ....*....|....*....|...
gi 6755338    238 DVCAICLEEYEDGDKLRILPCSH 260
Cdd:pfam13639   1 DECPICLEEFEEGDKVVVLPCGH 23

RING finger, H2 subclass, found in Arabidopsis thaliana RING-type E3 ubiquitin transferase BIG BROTHER (BB) and similar proteins; BB (also known as protein ENHANCER OF DA1-1 or EOD1) is an E3 ubiquitin-protein ligase that limits organ size, and possibly seed size, in a dose-dependent manner. It negatively regulates the duration of cell proliferation in leaves and petals independently of the major phytohormones (e.g. auxin, cytokinin, gibberellin, brassinosteroids, ethylene, abscisic acid, jasmonic acid), probably by targeting growth stimulators for degradation. It limits the proliferation of root meristematic cells. BB polyubiquitinates DA1. It is involved in the promotion of leaf senescence, in addition to its function in restricting plant growth. BB-related is an E3 ubiquitin-ligase probably involved in organ size regulation. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                        10        20
                ....*....|....*....|.
gi 6755338  240 CAICLEEYEDGDKLRILPCSH 260
Cdd:cd23115   7 CVICRLEYEEGEDLLTLPCKH 27

RING-finger-containing ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338   35 DILAYNFENASQTFEDLPARfgyrlpAEGLKGFLINSKPENACEPIVPPPLKDNSSGTFIvLIRRLDCNFDIKVLNAQRA 114
Cdd:COG5540  97 DLISGYFGDGDDGREYDETR------IPPPSRDLRGSGRKVRGSARQEVPSVEERNLVDR-CNRRGNETEEDPTRERRRT 169

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338  115 GYKAAIV---HNVDSDDLISMGSNDIDTLKKIDIPSVFIGESSANSLKDEFTYEKG------------------------ 167
Cdd:COG5540 170 RFKGVIRgseRNGETFRLHYMVAPDKVDPRSEGVEDPVTLTTSINVTWDGLGNTYQapsqsaeaqdetgdmfwprlsrfv 249

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755338  168 -GHIILVPELSLPLEYYL---------IPFLIIVGICLILIVIFmitkFVQDRHRNRRNRlrKDQLKKLPVHKFKKGDEY 237
Cdd:COG5540 250 gSRGFRVVFPRIPSQELRflfltqskgSRFNIILEIQINFDVGF----YSSSEAIPTTTT--KGSLKPLSIERAVEADKG 323

                       250       260
                ....*....|....*....|...
gi 6755338  238 DVCAICLEEYEDGDKLRILPCSH 260
Cdd:COG5540 324 VECAICMSNFIKNDRLRVLPCDH 346

RING finger, H2 subclass, found in RING finger protein 181 (RNF181) and similar proteins; RNF181, also known as HSPC238, is a platelet E3 ubiquitin-protein ligase containing a C3H2C3-type RING-H2 finger. It interacts with the KVGFFKR motif of platelet integrin alpha(IIb)beta3, suggesting a role for RNF181-mediated ubiquitination in integrin and platelet signaling. It also suppresses the tumorigenesis of hepatocellular carcinoma (HCC) through the inhibition of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling in the liver.

                        10        20
                ....*....|....*....|.
gi 6755338  240 CAICLEEYEDGDKLRILPCSH 260
Cdd:cd16669   2 CPICLLEFEEGETVKQLPCKH 22

RING finger, H2 subclass, found in RING finger proteins, RNF130, RNF149, RNF150 and similar proteins; This subfamily includes RING finger proteins, RNF130, RNF149 and RNF150, which belong to a larger PA-TM-RING ubiquitin ligase family that has been characterized by an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence. RNF130, also known as Goliath homolog (H-Goliath), is a paralog of RNF128. It is a transmembrane E3 ubiquitin-protein ligase expressed in leukocytes. It has a self-ubiquitination property and controls the development of T cell clonal anergy by ubiquitination. RNF133 is a testis-specific endoplasmic reticulum-associated E3 ubiquitin ligase that may play a role in sperm maturation through an ER-associated degradation (ERAD) pathway. RNF149, also known as DNA polymerase-transactivated protein 2, is an E3 ubiquitin-protein ligase that induces the ubiquitination of wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and promotes its proteasome-dependent degradation. RNF150 polymorphisms may be associated with chronic obstructive pulmonary disease (COPD) risk in the Chinese population. This subfamily also includes Drosophila melanogaster protein goliath (d-goliath), also known as protein g1, which is one of the founding members of the group. It was originally identified as a transcription factor involved in the embryo mesoderm formation.

                        10        20
                ....*....|....*....|.
gi 6755338  240 CAICLEEYEDGDKLRILPCSH 260
Cdd:cd16668   2 CAVCIEPYKPSDVIRILPCKH 22

RING finger, H2 subclass, found in RING finger protein 215 (RNF215) and similar proteins; This family includes uncharacterized protein RNF215 and similar proteins. Although its biological function remains unclear, RNF215 shares high sequence similarity with PA-TM-RING ubiquitin ligases, which have been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger.

                        10        20
                ....*....|....*....|...
gi 6755338  238 DVCAICLEEYEDGDKLRILPCSH 260
Cdd:cd16670   1 ESCAVCLDQFYKNQCLRVLPCLH 23

RING finger, H2 subclass, found in protein E3 ubiquitin-protein ligase Praja-1, Praja-2, and similar proteins; This family includes two highly similar E3 ubiquitin-protein ligases, Praja-1 and Praja-2. Praja-1, also known as RING finger protein 70, is a RING-H2 finger ubiquitin ligase encoded by gene PJA1, a novel human X chromosome gene abundantly expressed in the brain. It has been implicated in bone and liver development, as well as memory formation and X-linked mental retardation (MRX). Praja-1 interacts with and activates the ubiquitin-conjugating enzyme UbcH5B, and shows E2-dependent E3 ubiquitin ligase activity. It is a 3-deazaneplanocin A (DZNep)-induced ubiquitin ligase that directly ubiquitinates individual polycomb repressive complex 2 (PRC2) subunits in a cell free system, which leads to their proteasomal degradation. It also plays an important role in neuronal plasticity, which is the basis for learning and memory. Moreover, Praja-1 ubiquitinates embryonic liver fodrin (ELF) and Smad3, but not Smad4, in a transforming growth factor-beta (TGF-beta)-dependent manner. It controls ELF abundance through ubiquitin-mediated degradation, and further regulates TGF-beta signaling, which plays a key role in the suppression of gastric carcinoma. Praja-1 also regulates the transcription function of the homeodomain protein Dlx5 by controlling the stability of Dlxin-1, via a ubiquitin-dependent degradation pathway. Praja-2, also known as RING finger protein 131, NEURODAP1, or KIAA0438, is an E2-dependent E3 ubiquitin ligase that interacts with and activates the ubiquitin-conjugating enzyme UbcH5B. It functions as an A-kinase anchoring protein (AKAP)-like E3 ubiquitin ligase that plays a critical role in controlling cyclic AMP (cAMP)-dependent PKA activity and pro-survival signaling, and further promotes cell proliferation and growth. Praja-2 is also involved in protein sorting at the postsynaptic density region of axosomatic synapses and possibly plays a role in synaptic communication and plasticity. Together with the AMPK-related kinase SIK2 and the CDK5 activator CDK5R1/p35, it forms a SIK2-p35-PJA2 complex that plays an essential role for glucose homeostasis in pancreatic beta cell functional compensation. Praja-2 ubiquitylates and degrades Mob, a core component of NDR/LATS kinase and a positive regulator of the tumor-suppressor Hippo signaling. Both Praja-1 and Praja-2 contain a potential nuclear localization signal (NLS) and a C-terminal C3H2C3-type RING-H2 motif.

                        10        20
                ....*....|....*....|.
gi 6755338  240 CAICLEEYEDGDKLRILPCSH 260
Cdd:cd16465   2 CPICCSEYVKDEIATELPCHH 22

RING finger, H2 subclass, found in RING finger protein 165 (RNF165) and similar proteins; RNF165, also known as Arkadia-like 2, Arkadia2, or Ark2C, is an E3 ubiquitin ligase with homology to the C-terminal half of RNF111. It is expressed specifically in the nervous system, and can serve to amplify neuronal responses to specific signals. It acts as a positive regulator of bone morphogenetic protein (BMP)-Smad signaling that is involved in motor neuron (MN) axon elongation. RNF165 contains two serine rich domains, a nuclear localization signal, an NRG-TIER domain, and a C-terminal C3H2C3-type RING-H2 finger that is responsible for the enhancement of BMP-Smad1/5/8 signaling in the spinal cord.

                        10        20        30
                ....*....|....*....|....*....|
gi 6755338  234 GDEYDV---CAICLEEYEDGDKLRILPCSH 260
Cdd:cd16682   1 GEESDTdekCTICLSMLEDGEDVRRLPCMH 30

RING finger, H2 subclass, found in RING finger protein 128 (RNF128) and similar proteins; This subfamily includes RING finger proteins RNF128, RNF133, RNF148, and similar proteins, which belong to a larger PA-TM-RING ubiquitin ligase family that has been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger followed by a putative PEST sequence. RNF128, also known as gene related to anergy in lymphocytes protein (GRAIL), is a type 1 transmembrane E3 ubiquitin-protein ligase that is a critical regulator of adaptive immunity and development. It inhibits cytokine gene transcription, is expressed in anergic CD4+ T cells, and has been implicated in primary T cell activation, survival, and differentiation, as well as in T cell anergy and oral tolerance. It induces T cell anergy through the ubiquitination activity of its cytosolic RING finger. It regulates expression of the costimulatory molecule CD40L on CD4 T cells, and ubiquitinates the costimulatory molecule CD40 ligand (CD40L) during the induction of T cell anergy. Moreover, RNF128 interacts with the luminal/extracellular portion of both CD151 and the related tetraspanin CD81 via its PA domain, which promoted ubiquitination of cytosolic lysine residues. It also down-modulates the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. Furthermore, Rho guanine dissociation inhibitor (RhoGDI) has been identified as a potential substrate of RNF128, suggesting a role for Rho effector molecules in T cell anergy. In addition, RNF128 plays a role in environmental stress responses. It promotes environmental salinity tolerance in euryhaline tilapia. RNF133 is a testis-specific endoplasmic reticulum-associated E3 ubiquitin ligase that is mainly present in the cytoplasm of elongated spermatids. It may play a role in sperm maturation through an ER-associated degradation (ERAD) pathway. RNF148 is a testis-specific E3 ubiquitin ligase that is abundantly expressed in testes and slightly expressed in pancreas. Its expression is regulated by histone deacetylases.

                        10        20
                ....*....|....*....|...
gi 6755338  238 DVCAICLEEYEDGDKLRILPCSH 260
Cdd:cd16802   1 DSCAVCIEPYKPNDVVRILTCNH 23

RING finger, H2 subclass, found in RING finger protein 149 (RNF149) and similar proteins; RNF149, also known as DNA polymerase-transactivated protein 2, is an E3 ubiquitin-protein ligase that interacts with wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), a RING domain-containing E3 ubiquitin ligase involved in control of gene transcription, translation, cytoskeletal organization, cell adhesion, and epithelial development. RNF149 induces the ubiquitination of wild-type BRAF and promotes its proteasome-dependent degradation. Mutated RNF149 has been found in some human breast, ovarian, and colorectal cancers. RNF149 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                        10        20
                ....*....|....*....|.
gi 6755338  240 CAICLEEYEDGDKLRILPCSH 260
Cdd:cd16804   2 CAVCIENYKSKDVVRILPCKH 22

RING finger, H2 subclass, found in DAZ (deleted in azoospermia)-interacting protein 3 (DZIP3) and similar proteins; DZIP3, also known as RNA-binding ubiquitin ligase of 138 kDa (RUL138) or 2A-HUB protein, is an RNA-binding E3 ubiquitin-protein ligase that interacts with coactivator-associated arginine methyltransferase 1 (CARM1) and acts as a transcriptional coactivator of estrogen receptor (ER) alpha. It is also a histone H2A ubiquitin ligase that catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatorial component of the repression machinery required for repressing a specific chemokine gene expression program, critically modulating migratory responses to Toll-like receptors (TLR) activation. DZIP3 contains a C3H2C3-type RING-H2 finger at the C-terminus.

                        10        20
                ....*....|....*....|.
gi 6755338  240 CAICLEEYEDGDKLRILPCSH 260
Cdd:cd16460   3 CVICHEAFSDGDRLLVLPCAH 23