modified RING finger, H2 subclass (C3H2C2D-type), found in RING-box protein 1 (RBX1) and similar proteins; RBX1, also known as Hrt1, protein ZYP, RING finger protein 75 (RNF75), or regulator of cullins 1 (ROC1), is an E3 ubiquitin-protein ligase necessary for ubiquitin ligation activity of multimeric cullin (Cul)-RING E3 ligases (CRLs). RBX1-containing CRLs are involved in the NEDD8 pathway; RBX1 specifically regulates NEDD8ylation of Cul1-4. It can also bind and activate HIV-1 Vif-Cullin5 E3 ligase complex in vitro. Moreover, RBX1 is an essential element of Skp1/Cullin/F-box (SCF) E3-ubiquitin ligase complexes that target diverse proteins for proteasome-mediated degradation. It is a direct functional target of miR-194 and plays an important role in proliferation and migration of gastric cancer (GC) cells. RBX1 is also an essential component of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex that functions as a regulator of NFE2-related factor 2 (NRF2) and plays a key role in NRF2 pathway deregulation in multiple tumor types, including ovarian carcinomas (OVCA) and papillary thyroid carcinoma (PTC). Furthermore, RBX1 associates with DDB1, Cul4A, and Fbxw5 to form the Fbxw5-DDB1-Cul4A-Rbx1 complex that may function as a dual SUMO/ubiquitin ligase suppressing c-Myb activity through sumoylation or ubiquitination. RBX1 contains a C-terminal modified RING-H2 finger that is of C3H2C2D-type, rather than the canonical C3H2C3-type. The modified RING-H2 finger is essential for its ligase activity.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 124426661 27 DNCAICKNHIMEKCIECDAQEG---QGECIVAWGTCNHAYHFHCIERWLKNRQTCPLDNRNW 85
Cdd:cd16485   1 DNCAICRNHIMDLCIECQANQAsatSEECTVAWGVCNHAFHFHCISRWLKTRQVCPLDNREW 62

N1R/p28-like protein; Provisional

                         10        20
                 ....*....|....*....|..
gi 124426661  59 CNHAYHFHCIERWLKNRQTCPL 80
Cdd:PHA02929 200 CNHVFCIECIDIWKKEKNTCPV 221

modified RING finger, H2 subclass (C3H2C2D-type), found in RING-box protein 1 (RBX1) and similar proteins; RBX1, also known as Hrt1, protein ZYP, RING finger protein 75 (RNF75), or regulator of cullins 1 (ROC1), is an E3 ubiquitin-protein ligase necessary for ubiquitin ligation activity of multimeric cullin (Cul)-RING E3 ligases (CRLs). RBX1-containing CRLs are involved in the NEDD8 pathway; RBX1 specifically regulates NEDD8ylation of Cul1-4. It can also bind and activate HIV-1 Vif-Cullin5 E3 ligase complex in vitro. Moreover, RBX1 is an essential element of Skp1/Cullin/F-box (SCF) E3-ubiquitin ligase complexes that target diverse proteins for proteasome-mediated degradation. It is a direct functional target of miR-194 and plays an important role in proliferation and migration of gastric cancer (GC) cells. RBX1 is also an essential component of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex that functions as a regulator of NFE2-related factor 2 (NRF2) and plays a key role in NRF2 pathway deregulation in multiple tumor types, including ovarian carcinomas (OVCA) and papillary thyroid carcinoma (PTC). Furthermore, RBX1 associates with DDB1, Cul4A, and Fbxw5 to form the Fbxw5-DDB1-Cul4A-Rbx1 complex that may function as a dual SUMO/ubiquitin ligase suppressing c-Myb activity through sumoylation or ubiquitination. RBX1 contains a C-terminal modified RING-H2 finger that is of C3H2C2D-type, rather than the canonical C3H2C3-type. The modified RING-H2 finger is essential for its ligase activity.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 124426661 27 DNCAICKNHIMEKCIECDAQEG---QGECIVAWGTCNHAYHFHCIERWLKNRQTCPLDNRNW 85
Cdd:cd16485   1 DNCAICRNHIMDLCIECQANQAsatSEECTVAWGVCNHAFHFHCISRWLKTRQVCPLDNREW 62

RING finger, H2 subclass, found in RING-box protein 2 (RBX2) and similar proteins; RBX2, also known as CKII beta-binding protein 1 (CKBBP1), RING finger protein 7 (RNF7), regulator of cullins 2 (ROC2), or sensitive to apoptosis gene protein (SAG), is an E3 ubiquitin-protein ligase that protects cells from apoptosis, confers radioresistance, and plays an essential and non-redundant role in embryogenesis and vasculogenesis. It promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1alpha, IkappaBalpha, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. RBX2 is necessary for ubiquitin ligation activity of the multimeric cullin (Cul)-RING E3 ligases (CRLs). RBX2-containing CRLs are involved in the NEDD8 pathway and RBX2 specifically regulates NEDD8ylation of Cul5. It can bind and activate the HIV-1 Vif-Cullin5 E3 ligase complex in vitro. It is also a substrate of NEDD4-1 E3 ubiquitin ligase and mediates NEDD4-1 induced chemosensitization. The inactivation of RBX2 E3 ubiquitin ligase activity triggers senescence and inhibits Kras-induced immortalization. Endothelial deletion of RBX2 causes embryonic lethality and blocks tumor angiogenesis, and may have potential use in anti-angiogenesis therapy of human cancers. Moreover, as a component of the Cullin 5-RING E3 ubiquitin ligase (CRL5) complex, RBX2 regulates neuronal migration through different CRL5 adaptors, such as SOCS7. RBX2 also functions as a redox inducible antioxidant protein that scavenges oxygen radicals by forming inter- and intra-molecular disulfide bonds when acting alone. It contains a C-terminal C3H2C3-type RING-H2 finger that is essential for its ligase activity.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 124426661 27 DNCAICKNHIMEKCIECDAQEGQGECIVAWGTCNHAYHFHCIERWLKNRQTCPLDNRNW 85
Cdd:cd16466   2 DTCAICRVQVMDACLRCQAENKQEDCVVVWGECNHSFHNCCMSLWVKQNNRCPLCQQDW 60

RING finger, H2 subclass, found in anaphase-promoting complex subunit 11 (APC11) and similar proteins; APC11, also known as cyclosome subunit 11, or hepatocellular carcinoma-associated RING finger protein, is a C3H2C3-type RING-H2 protein that facilitates ubiquitin chain formation by recruiting ubiquitin-charged ubiquitin conjugating enzymes (E2) through its RING-H2 domain. APC11 and its partner, the cullin-like subunit APC2, form the dynamic catalytic core of the gigantic, multisubunit 1.2-MDa anaphase-promoting complex/cyclosome (APC), also known as the cyclosome, which is a ubiquitin-protein ligase (E3) composed of at least 12 subunits and controls cell division by ubiquitinating cell cycle regulators, such as cyclin B and securin, to drive their timely degradation. APC11 can be inhibited by hydrogen peroxide, which may contribute to the delay in cell cycle progression through mitosis that is characteristic of cells subjected to oxidative stress. APC11 contains a canonical RING-H2-finger that coordinate two Zn2+ ions. In addition, it contains a third Zn2+-binding site that is not essential for its ligase activity.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 124426661 27 DNCAICKNHIMEKCIECDAQegQGECIVAWGTCNHAYHFHCIERWLKN---RQTCPLDNRNWEY 87
Cdd:cd16456   2 DVCGICRMAFDGCCPDCKFP--GDDCPLVWGKCSHCFHMHCILKWLNSqqvQQHCPMCRQEWKF 63

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 124426661 58 TCNHAYHFHCIERWLKNRQTCPL 80
Cdd:cd16454  19 PCNHLFHKDCIDPWLEQHNTCPL 41

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 124426661 59 CNHAYHFHCIERWLKNRQTCPLDNR 83
Cdd:cd16674  21 CSHEYHVHCIDRWLSENSTCPICRR 45

RING finger, H2 subclass, found in E3 ubiquitin-protein ligase RNF6 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. Moreover, RNF6 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 also binds and upregulates the Inha promoter, and functions as a transcription regulatory protein in the mouse sertoli cell. RNF6 also acts as a potential tumor suppressor gene involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC). RNF6 contains an N-terminal coiled-coil domain, a Lys-X-X-Leu/Ile-X-X-Leu/Ile (KIL) motif, and a C-terminal C3H2C3-type RING-H2 finger which is responsible for its ubiquitin ligase activity. The KIL motif is present in a subset of RING-H2 proteins from organisms as evolutionarily diverse as human, mouse, chicken, Drosophila, Caenorhabditis elegans, and Arabidopsis thaliana.

                        10        20
                ....*....|....*....|..
gi 124426661 59 CNHAYHFHCIERWLKNRQTCPL 80
Cdd:cd16673  21 CAHEFHIHCIDRWLSENSTCPI 42

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
                ....*....|....*....|..
gi 124426661 59 CNHAYHFHCIERWLKNRQTCPL 80
Cdd:cd16680  28 CNHEFHTKCVDKWLKTNRTCPI 49

Ring finger domain;

                         10        20
                 ....*....|....*....|..
gi 124426661  59 CNHAYHFHCIERWLKNRQTCPL 80
Cdd:pfam13639 21 CGHHFHRECLDKWLRSSNTCPL 42

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
                ....*....|....*....|..
gi 124426661 59 CNHAYHFHCIERWLKNRQTCPL 80
Cdd:cd16461  21 CKHAFHKECIDEWLKSNSTCPL 42

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
                ....*....|....*....|....*.
gi 124426661 59 CNHAYHFHCIERWL-KNRQTCPLDNR 83
Cdd:cd16665  21 CSHAYHCKCIDPWLtKNKRTCPVCKR 46

RING finger, H2 subclass, found in Arabidopsis thaliana RING-H2 finger A1a (RHA1A), A1b (RHA1B) and similar proteins; This subfamily includes Arabidopsis thaliana RHA1A, RHA1B and XERICO. RHA1A is a probable E3 ubiquitin-protein ligase that may possess E3 ubiquitin ligase activity in vitro. RHA1B possesses E3 ubiquitin-protein ligase activity when associated with the E2 enzyme UBC8 in vitro. XERICO functions on abscisic acid homeostasis at post-translational level, probably through ubiquitin/proteasome-dependent substrate-specific degradation. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 124426661 40 CIECDAQEGQGECIVAWGTCNHAYHFHCIERWLK-NRQTCPL 80
Cdd:cd23121   4 CAICLSDFNSDEKLRQLPKCGHIFHHHCLDRWIRyNKITCPL 45

RING finger, H2 subclass, found in RING finger proteins RNF139, RNF145, 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. RNF145 is an uncharacterized RING finger protein encoded by the RNF145 gene, which is expressed in T lymphocytes, and its expression is altered in acute myelomonocytic and acute promyelocytic leukemias. Although its biological function remains unclear, RNF145 shows high sequence similarity with RNF139. Both RNF139 and RNF145 contain a C3H2C3-type RING-H2 finger with possible E3-ubiquitin ligase activity.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 124426661 27 DNCAICKNHIMEKCIEcdaqegqgecivawgTCNHAYHFHCIERWLKNRQTCPL 80
Cdd:cd16476   1 DVCAICYQEMKEARIT---------------PCNHFFHGLCLRKWLYVQDTCPL 39

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
                ....*....|....*....|..
gi 124426661 59 CNHAYHFHCIERWLKNRQTCPL 80
Cdd:cd16679  41 CNHEFHAKCVDKWLKANRTCPI 62

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
                ....*....|....*....|...
gi 124426661 59 CNHAYHFHCIERWL-KNRQTCPL 80
Cdd:cd16797  21 CSHAYHSKCVDPWLtQTKKTCPV 43

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        30        40
                ....*....|....*....|....*....|....*....|..
gi 124426661 38 EKCIECDAQEGQGECIVAWgTCNHAYHFHCIERWLKNRQTCP 79
Cdd:cd16460   1 TPCVICHEAFSDGDRLLVL-PCAHKFHTQCIGPWLDGQQTCP 41

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 124426661 59 CNHAYHFHCIERWLKNRQTCPLDNRN 84
Cdd:cd16670  21 CLHEFHRDCVDPWLLLQQTCPLCKRN 46