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        40
                 ....*....|....*....|....*....|....*....|....*..
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQApRRSCPVCKQ 353
Cdd:cd16665    1 DVCAICLDDYEEGDKLRILPCSHAYHCKCIDPWLTKN-KRTCPVCKR 46

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        40
                 ....*....|....*....|....*....|....*....|....*..
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQApRRSCPVCKQ 353
Cdd:cd16665    1 DVCAICLDDYEEGDKLRILPCSHAYHCKCIDPWLTKN-KRTCPVCKR 46

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 150170725 107 NSSSVD--FADLPALFGVPLAPEGIRGYL-----MEVKPANACHPIeaprLGNRSL-GAIVLIRRYDCTFDLKVLNAQRA 178
Cdd:NF038113 416 APGSLAgrYPGVRAGFGPRLPDAPITGDLalatdSSPDPNDGCDPI----LNAAALaGKIAVIRRGSCEFAVKVLNAQNA 491

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 150170725 179 GFEAAIVHNVHSDDLVSMThvYEDLRGQIAIPSVFVSEAASQDLRVILGCNKSAHALLLPDDP 241
Cdd:NF038113 492 GAIAVIIVNNVPGEPIVMG--GGDTGPPITIPSIMISQADGEAIITALNNGETVNVTLKDDGS 552

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

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQApRRSCPVCKQSV 355
Cdd:COG5540  326 CAICMSNFIKNDRLRVLPCDHRFHVGCVDKWLLGY-SNKCPVCRTAI 371

myxosortase-dependent M36 family metallopeptidase; Members of this bacterial protein family have an M36 family metallopeptidase domain, like fungalysin (see PF02128), and a C-terminal MYXO-CTERM domain (see TIGR03901), suggesting processing and surface-anchoring by the still-unknown putative transpeptidase, myxosortase. Members of this family include MXAN_3564 (mepA), part of the effector cargo of outer membrane vesicles that the species produces in large numbers during predation on other microbes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 150170725   90 SLLQVPAQAVVRAVLEdnSSSVDFAdlPALFGVP----LAPEGIrgylmeVKPANACHPIEAPrlgNRSLGAIVLIRRYD 165
Cdd:NF038112  489 QTLTVTAPASLAGVYE--AGSASFG--PQAFDVTgdvvLAPDGT------GSDTDGCTPFTNA---AEVAGKIALIDRGT 555

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 150170725  166 CTFDLKVLNAQRAGFEAAIVHNVHSDDLVSMTHvyEDLRgqIAIPSVFVSEAASQDLR 223
Cdd:NF038112  556 CDFTVKALNAQNAGAIGVIIANNAAGAAPGLGG--TDPA--VTIPALSITQADGNAWK 609

5L protein; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 150170725 306 NDLCAICLDEYEEGDQLKIlpCSHTY---HCKCIDPWFSQAPRRSCPVCKQ--SVAATEDSFDSTTYSFRDEDPSL 376
Cdd:PHA02862   2 SDICWICNDVCDERNNFCG--CNEEYkvvHIKCMQLWINYSKKKECNLCKTkyNIKKTYVSFKKWNWCFNDKKTTL 75

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        40
                 ....*....|....*....|....*....|....*....|....*..
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQApRRSCPVCKQ 353
Cdd:cd16665    1 DVCAICLDDYEEGDKLRILPCSHAYHCKCIDPWLTKN-KRTCPVCKR 46

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        40
                 ....*....|....*....|....*....|....*....|....*....
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQApRRSCPVCKQSV 355
Cdd:cd16796    9 DVCAICLDEYEEGDKLRILPCSHAYHCKCVDPWLTKT-KKTCPVCKQKV 56

RING finger, H2 subclass, found in RING finger protein 103 (RNF103) and similar proteins; RNF103, also known as KF-1 or zinc finger protein 103 homolog (Zfp-103), is an endoplasmic reticulum (ER)-resident E3 ubiquitin-protein ligase that is widely expressed in many different organs, including brain, heart, kidney, spleen, and lung. It is involved in the ER-associated degradation (ERAD) pathway by interacting with components of the ERAD pathway, including Derlin-1 and VCP. RNF103 contains several hydrophobic regions at its N-terminal and middle regions, as well as a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 150170725 305 HNDLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQaPRRSCPVCKQSV 355
Cdd:cd16473    3 ECEECAICLENYQNGDLLRGLPCGHVFHQNCIDVWLER-DNHCCPVCRWPV 52

RING finger, H2 subclass, found in E3 ubiquitin-protein ligase RNF6, RNF12, and similar proteins; RNF6 is an androgen receptor (AR)-associated protein that induces AR ubiquitination and promotes AR transcriptional activity. RNF6-induced ubiquitination may regulate AR transcriptional activity and specificity by modulating cofactor recruitment. RNF6 is overexpressed in hormone-refractory human prostate cancer tissues and required for prostate cancer cell growth under androgen-depleted conditions. RNF6 also regulates local serine/threonine kinase LIM kinase 1 (LIMK1) levels in axonal growth cones. RNF6-induced LIMK1 polyubiquitination is mediated via K48 of ubiquitin and leads to proteasomal degradation of the kinase. RNF6 binds and upregulates the Inha promoter, and functions as a transcription regulatory protein in the mouse sertoli cell. It acts as a potential tumor suppressor gene involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC). 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. Both RNF6 and RNF12 contain a well conserved C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCK 352
Cdd:cd16467    2 CTICLGEYETGEKLRRLPCSHEFHSECVDRWLKE--NSSCPICR 43

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 150170725 138 PANACHPIEAprlGNRSLGAIVLIRRYDCTFDLKVLNAQRAGFEAAIVHN-VHSDDLVSMThvyeDLRGQIAIPSVFVSE 216
Cdd:cd04818   26 NTDGCTAFTN---AAAFAGKIALIDRGTCNFTVKVLNAQNAGAIAVIVANnVAGGAPITMG----GDDPDITIPAVMISQ 98

                         90       100
                 ....*....|....*....|
gi 150170725 217 AASQDLRVILGCNKSAHALL 236
Cdd:cd04818   99 ADGDALKAALAAGGTVTVTL 118

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        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCKQSVAAT 358
Cdd:cd16674    3 CSVCITEYTEGNKLRKLPCSHEYHVHCIDRWLSE--NSTCPICRRAVLAS 50

RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins; This subfamily includes RING finger proteins RNF38, RNF44, and similar proteins. RNF38 is a nuclear E3 ubiquitin protein ligase that plays a role in regulating p53. RNF44 is an uncharacterized RING finger protein that shows high sequence similarity to RNF38. Both RNF38 and RNF44 contain a coiled-coil motif, a KIL motif (Lys-X2-Ile/Leu-X2-Ile/Leu, X can be any amino acid), and a C3H2C3-type RING-H2 finger. In addition, RNF38 harbors two potential nuclear localization signals.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCK 352
Cdd:cd16472    5 CVVCMCDYEKRQLLRVLPCSHEFHAKCIDKWLKT--NRTCPICR 46

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 150170725 138 PANACHPIEAPRLGNRSLGAIVLIRRYDCTFDLKVLNAQRAGFEAAIVHNVHSDDLVSMTHVYEDLRGqIAIPSVFVSEA 217
Cdd:cd00538   29 PLVGCGYGTTDDSGADVKGKIVLVRRGGCSFSEKVKNAQKAGAKAVIIYNNGDDPGPQMGSVGLESTD-PSIPTVGISYA 107

                         90
                 ....*....|....*....
gi 150170725 218 ASQDLRVILGCNKSAHALL 236
Cdd:cd00538  108 DGEALLSLLEAGKTVTVDL 126

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 150170725  307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQAPRrsCPVCK 352
Cdd:pfam13639   1 DECPICLEEFEEGDKVVVLPCGHHFHRECLDKWLRSSNT--CPLCR 44

RING finger, H2 subclass, found in rice E3 ubiquitin-protein ligase EL5 and similar proteins; EL5, also known as protein ELICITOR 5, is an E3 ubiquitin-protein ligase containing an N-terminal transmembrane domain and a C3H2C3-type RING-H2 finger that is a binding site for ubiquitin-conjugating enzyme (E2). It can be rapidly induced by N-acetylchitooligosaccharide elicitor. EL5 catalyzes polyubiquitination via the Lys48 residue of ubiquitin, and thus plays a crucial role as a membrane-anchored E3 in the maintenance of cell viability after the initiation of root primordial formation in rice. It also acts as an anti-cell death enzyme that might be responsible for mediating the degradation of cytotoxic proteins produced in root cells after the actions of phytohormones. Moreover, EL5 interacts with UBC5b, a rice ubiquitin carrier protein, through its RING-H2 finger. EL5 is an unstable protein, and its degradation is regulated by the C3H2C3-type RING-H2 finger in a proteasome-independent manner.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 150170725 309 CAICLDEYEEGDQLKILP-CSHTYHCKCIDPWFSQapRRSCPVC 351
Cdd:cd16461    2 CAICLSDYENGEELRRLPeCKHAFHKECIDEWLKS--NSTCPLC 43

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        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCKQSV 355
Cdd:cd16668    2 CAVCIEPYKPSDVIRILPCKHIFHKSCVDPWLLE--HRTCPMCKLDI 46

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        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFsqAPRRSCPVCK 352
Cdd:cd16802    1 DSCAVCIEPYKPNDVVRILTCNHLFHKNCIDPWL--LEHRTCPMCK 44

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        30        40
                 ....*....|....*....|....*....|....*....|....
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQAprRSCPVCK 352
Cdd:cd16669    2 CPICLLEFEEGETVKQLPCKHSFHSDCILPWLGKT--NSCPLCR 43

RING finger, H2 subclass, found in RING finger protein 130 (RNF130) and similar proteins; RNF130, also known as Goliath homolog (H-Goliath), is a paralog of RNF128, also known as gene related to anergy in lymphocytes protein (GRAIL). 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. RNF130 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        40
                 ....*....|....*....|....*....|....*....|....*....
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCKQSV 355
Cdd:cd16803    1 DHCAVCIEGYKQNDVVRILPCKHVFHKSCVDPWLNE--HCTCPMCKLNI 47

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        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFsqAPRRSCPVCKQSV 355
Cdd:cd16670    1 ESCAVCLDQFYKNQCLRVLPCLHEFHRDCVDPWL--LLQQTCPLCKRNI 47

RING finger, H2 subclass, found in Arabidopsis thaliana MED25-binding RING-H2 protein (MBR) and similar proteins; This subfamily includes MBR1 and MBR2 (also called HAL3-interacting protein 1 or AtHIP1). They are E3 ubiquitin-protein ligases that function as regulators of MED25 stability by targeting MED25 for degradation in a RING-H2-dependent manner. Proteasome-dependent degradation of MED25 seems to activate its function as a positive regulator of FLOWERING LOCUS T (FT) and is important to induce the expression of FT, and consequently to promote flowering. MBR2 may also function downstream of HAL3 and be required for HAL3-regulated plant growth. Activation of MBR2 by HAL3 may lead to the degradation of cell cycle suppressors, resulting in enhancement of cell division and plant growth. Both MBR1 and MBR2 contain a C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCK 352
Cdd:cd23113    5 CCICQEEYEEGDELGTIECGHEYHSDCIKQWLVQ--KNLCPICK 46

RING finger, H2 subclass, found in RING finger protein 44 (RNF44) and similar proteins; RNF44 is an uncharacterized RING finger protein that shows high sequence similarity with RNF38, which is a nuclear E3 ubiquitin protein ligase that plays a role in regulating p53. RNF44 contains a coiled-coil motif, a KIL motif (Lys-X2-Ile/Leu-X2-Ile/Leu, X can be any amino acid), and a C3H2C2-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 150170725 308 LCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCK 352
Cdd:cd16680    9 LCVVCFSDFESRQLLRVLPCNHEFHTKCVDKWLKT--NRTCPICR 51

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        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCKQS 354
Cdd:cd16799    2 CAICLEKYIDGEELRVIPCTHRFHKKCVDPWLLQ--HHTCPHCRHN 45

RING finger, H2 subclass, found in RING finger protein 24 (RNF24) 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. RNF24 contains an N-terminal transmembrane domain and a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCKQSV 355
Cdd:cd16675    1 EICAVCLEEFKPKDELGICPCKHAFHRKCLIKWLEV--RKVCPLCNMPV 47

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 150170725 156 GAIVLIRRYDCTFDLKVLNAQRAGFEAAIVHNvHSDDLVSMThvyedLRGQIAIPSVFVS 215
Cdd:cd02133   48 GKIALIQRGEITFVEKIANAKAAGAVGVIIYN-NVDGLIPGT-----LGEAVFIPVVFIS 101

RING finger, H2 subclass, found in RING finger protein 111 (RNF111) and similar proteins; RNF111, also known as Arkadia, is a nuclear E3 ubiquitin-protein ligase that targets intracellular effectors and modulators of transforming growth factor beta (TGF-beta)/Nodal-related signaling for polyubiquitination and proteasome-dependent degradation. It acts as an amplifier of Nodal signals, and enhances the dorsalizing activity of limiting amounts of Xnr1, a Nodal homolog, and requires Nodal signaling for its function. The loss of RNF111 results in early embryonic lethality, with defects attributed to compromised Nodal signaling. RNF111 also regulates tumor metastasis by modulation of the TGF-beta pathway. Its ubiquitination can be modulated by the four and a half LIM-only protein 2 (FHL2) that activates TGF-beta signal transduction. Furthermore, RNF111 interacts with the clathrin-adaptor 2 (AP2) complex and regulates endocytosis of certain cell surface receptors, leading to modulation of epidermal growth factor (EGF) and possibly other signaling pathways. In addition, RNF111 has been identified as a small ubiquitin-like modifier (SUMO)-binding protein with clustered SUMO-interacting motifs (SIMs) that together form a SUMO-binding domain (SBD). It thus functions as a SUMO-targeted ubiquitin ligase (STUbL) that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response, as well as triggers degradation of signal-induced polysumoylated proteins, such as the promyelocytic leukemia protein (PML). The N-terminal half of RNF111 harbors three SIMs. Its C-terminal half show high sequence similarity with RING finger protein 165 (RNF165), where it contains two serine rich domains, two nuclear localization signals, an NRG-TIER domain, and a C-terminal C3H2C3-type RING-H2 finger that is required for polyubiqutination and proteasome-dependent degradation of phosphorylated forms of Smad2/3 and three major negative regulators of TGF-beta signaling, Smad7, SnoN and c-Ski.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCKQSVAA 357
Cdd:cd16681   13 CTICLSILEEGEDVRRLPCMHLFHQVCVDQWLIT--NKKCPICRVDIEA 59

RING finger, H2 subclass, found in RING finger protein 126 (RNF126) and similar proteins; RNF126 is a Bag6-dependent E3 ubiquitin ligase that is involved in the mislocalized protein (MLP) pathway of quality control. It regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR). Moreover, RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation, and could be a novel therapeutic target in breast and prostate cancers. It is also able to ubiquitylate cytidine deaminase (AID), a poorly soluble protein that is essential for antibody diversification. In addition, RNF126 and the related protein, RNF115 associate with the epidermal growth factor receptor (EGFR) and promote ubiquitylation of EGFR, suggesting they play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors. RNF126 contains an N-terminal BCA2 Zinc-finger domain (BZF), the AKT-phosphorylation sites, and the C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCKQ 353
Cdd:cd16801    2 CPVCKEDYTVGENVRQLPCNHLFHNDCIVPWLEQ--HDTCPVCRK 44

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 150170725 135 EVKPANACHPIEAPRLGNRslgaIVLIRRYDCTFDLKVLNAQRAGFEAAIV-HNVHSDDLVSMTHVYEDlrGQIAIPSVF 213
Cdd:cd04813   23 KVSPTDACSLQEHAEIDGK----VALVLRGGCGFLDKVMWAQRRGAKAVIVgDDEPGRGLITMFSNGDT--DNVTIPAMF 96

                         90
                 ....*....|...
gi 150170725 214 VSEAASQDLRVIL 226
Cdd:cd04813   97 TSRTSYHLLSSLL 109

RING finger, H2 subclass, found in RING finger protein 122 (RNF122) and similar proteins; 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. It interacts with calcium-modulating cyclophilin ligand (CAML), which is not a substrate, but a stabilizer of RNF122. RNF122 contains an N-terminal transmembrane domain and a C-terminal C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCPVCKQSV 355
Cdd:cd16676    3 CAVCLEDFKTKDELGVLPCQHAFHRKCLVKWLEI--RCVCPMCNKPI 47

RING finger, H2 subclass, found in RING finger protein 38 (RNF38) and similar proteins; RNF38 is a nuclear E3 ubiquitin protein ligase that is widely expressed throughout the human body, and is especially highly expressed in the heart, brain, placenta and the testis. It recognizes p53 as a substrate for ubiquitination, and thus plays a role in regulating p53. The overexpression of RNF38 increases p53 ubiquitination and alters p53 localization. It is also capable of autoubiquitination. RNF38 expression is negatively regulated by the serotonergic system. Induction of RNF38 may be involved in the anxiety-like behavior or non-cell autonomy in Oryzias latipes by the decline of serotonin (5-HT) levels. RNF38 contains a coiled-coil motif, a KIL motif (Lys-X2-Ile/Leu-X2-Ile/Leu, X can be any amino acid), a C3H2C3-type RING-H2 finger, as well as two potential nuclear localization signals.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 150170725 308 LCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSqaPRRSCPVCK 352
Cdd:cd16679   22 LCVVCMCDFESRQLLRVLPCNHEFHAKCVDKWLK--ANRTCPICR 64

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 150170725   309 CAICLDEYEEgdQLKILPCSHTYHCKCIDPWFSQAPRRsCPVC 351
Cdd:smart00184   1 CPICLEEYLK--DPVILPCGHTFCRSCIRKWLESGNNT-CPIC 40

Modified RING-CH finger, H2 subclass (C4HC2H-type), found in zinc/RING finger protein 2 (ZNRF2) and similar proteins; ZNRF2, also known as protein Ells2 or RING finger protein 202 (RNF202), is an E3 ubiquitin-protein ligase that is highly expressed in the nervous system during development and is present in presynaptic plasma membranes. It is N-myrisotoylated and is also located in the endosome-lysosome compartment in fibroblasts. It contains an N-terminal MAGE domain, and a special C-terminal domain that combines a zinc finger and a modified C4HC2H-type RING-CH finger, rather than the typical C4HC3-type RING-CH finger, which is a variant of RING-H2 finger. Only the RING finger of the zinc finger-RING finger motif is required for its E3 ubiquitin ligase activity. Together with its sister protein ZNRF1, ZNRF2 regulates the ubiquitous Na+/K+ pump (Na+/K+ATPase).

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 150170725 309 CAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQapRRSCP 349
Cdd:cd16695   13 CAICLEELQQGDTIARLPCLCIYHKGCIDEWFEV--NRSCP 51

RING finger, H2 subclass, found in Saccharomyces cerevisiae RING-H2 zinc finger protein RHA2B and similar proteins; RHA2B is an E3 ubiquitin-protein ligase involved in the positive regulation of abscisic acid (ABA) signaling and responses to salt and osmotic stresses during seed germination and early seedling development. It acts additively with RHA2A in regulating ABA signaling and drought response. RHA2B contains a C3H2C3-type RING-H2 finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFsQAPRRSCPVCK 352
Cdd:cd23123    1 SDCCICLDKLKTGEEVKKLDCRHKFHKQCIEGWL-KHLNFNCPLCR 45

myxosortase-dependent M36 family metallopeptidase; Members of this bacterial protein family have an M36 family metallopeptidase domain, like fungalysin (see PF02128), and a C-terminal MYXO-CTERM domain (see TIGR03901), suggesting processing and surface-anchoring by the still-unknown putative transpeptidase, myxosortase. Members of this family include MXAN_3564 (mepA), part of the effector cargo of outer membrane vesicles that the species produces in large numbers during predation on other microbes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 150170725   90 SLLQVPAQAVVRAVLEdnSSSVDFAdlPALFGVP----LAPEGIrgylmeVKPANACHPIEAPrlgNRSLGAIVLIRRYD 165
Cdd:NF038112  489 QTLTVTAPASLAGVYE--AGSASFG--PQAFDVTgdvvLAPDGT------GSDTDGCTPFTNA---AEVAGKIALIDRGT 555

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 150170725  166 CTFDLKVLNAQRAGFEAAIVHNVHSDDLVSMTHvyEDLRgqIAIPSVFVSEAASQDLR 223
Cdd:NF038112  556 CDFTVKALNAQNAGAIGVIIANNAAGAAPGLGG--TDPA--VTIPALSITQADGNAWK 609

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 150170725 123 PLAPEG-IRGYLMEVkPANACHPIEAPRlgnRSLGAIVLIRRYDCTFDLKVLNAQRAGFEAAIVHN 187
Cdd:cd02130   15 TYSPAGeVTGPLVVV-PNLGCDAADYPA---SVAGNIALIERGECPFGDKSALAGAAGAAAAIIYN 76

RING finger, H2 subclass, found in RING finger protein 139 (RNF139) and similar proteins; RNF139, also known as translocation in renal carcinoma on chromosome 8 protein (TRC8), is an endoplasmic reticulum (ER)-resident multi-transmembrane protein that functions as a potent growth suppressor in mammalian cells, inducing G2/M arrest, decreased DNA synthesis and increased apoptosis. It is a tumor suppressor that has been implicated in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control. A mutation in RNF139 has been identified in families with hereditary renal (RCC) and thyroid cancers. RNF139 physically and functionally interacts with von Hippel-Lindau (VHL), which is part of an SCF related E3-ubiquitin ligase complex with "gatekeeper" function in renal carcinoma and is defective in most sporadic clear-cell renal cell carcinomas (ccRCC). It suppresses growth and functions with VHL in a common pathway. RNF139 also suppresses tumorigenesis by targeting heme oxygenase-1 for ubiquitination and degradation. Moreover, RNF139 is a target of Translin (TSN), a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells, suggesting a role of RNF139 in dysgerminoma. In addition, RNF139 forms an integral part of a novel multi-protein ER complex, containing MHC I, US2, and signal peptide peptidase, which is associated with the ER-associated degradation (ERAD) pathway. It is required for the ubiquitination of MHC class I molecules before dislocation from the ER. As a novel sterol-sensing ER membrane protein, RNF139 hinders sterol regulatory element-binding protein-2 (SREBP-2) processing through interaction with SREBP-2 and SREBP cleavage-activated protein (SCAP), regulating its own turnover rate via its E3 ubiquitin ligase activity. RNF139 shows two regions of similarity with the receptor for sonic hedgehog (SHH), Patched. The first region corresponds to the second extracellular domain of Patched, which is involved in binding SHH. The second region is a putative sterol-sensing domain (SSD). The C-terminal half of RNF139 contains a C3H2C3-type RING-H2 finger with E3-ubiquitin ligase activity in vitro.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 150170725 306 NDLCAICLDEYeeGDQLKILPCSHTYHCKCIDPWFSqaPRRSCPVCKQSVAATED 360
Cdd:cd16683    4 DDVCAICYQEF--TTSARITPCNHYFHALCLRKWLY--IQDTCPMCHQKVYIEDD 54

RING finger, H2 subclass, found in Arabidopsis thaliana RING-H2 zinc finger protein RHF2A and similar proteins; RHF2A is an E3 ubiquitin-protein ligase involved in the positive regulation of the gametogenesis progression. It is required for the degradation of KRP6, a cyclin-dependent kinase inhibitor which accumulates during meiosis and blocks the progression of subsequent mitoses during gametophytes development. It functions in association with RHF1A. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 150170725 307 DLCAICLDEYEEGDQLKILPCSHTYHCKCIDPWFSQAprRSCPVCKQSVA 356
Cdd:cd23122   12 DACSICLESFCEADPATVTSCKHEYHLQCILEWSQRS--KECPMCWQALS 59

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 150170725 117 PALFGVPLAP-EGIRGYLMEVKPANACHPIEAPRLgnrSLGAIVLIRRYDCTFDLKVLNAQRAGFEAAIV----HNVHSD 191
Cdd:cd02126    4 PAQFGMDLTGdKAGVGRVVKAKPYRACSEITNAEE---VKGKIAIMERGDCMFVEKARRVQKAGAIGGIVidnnEGSSSD 80