RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130390333   1 MRIELTEVHGVFNWVWDIPKnedrldesmadedEDVCGICRASYHAPCPNCRYPGESCAIVLGRCGHNFHVHCISRWVDT 80
Cdd:pfam12861   1 MKVKIKEWNAVATWLWDVPS-------------DDVCGICRVSFDGTCPDCKFPGDDCPLVWGKCSHNFHMHCILKWLHT 67

                          90
                  ....*....|....*.
gi 2130390333  81 PTSKGLCPMCRQKFQL 96
Cdd:pfam12861  68 ETSKGLCPMCRQTFKF 83

Anaphase-promoting complex subunit 11 RING-H2 finger; Apc11 is one of the subunits of the anaphase-promoting complex or cyclosome. The APC subunits are cullin family proteins with ubiquitin ligase activity. Polyubiquitination marks proteins for degradation by the 26S proteasome and is carried out by a cascade of enzymes that includes ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). Apc11 acts as an E3 enzyme and is responsible for recruiting E2s to the APC and for mediating the subsequent transfer of ubiquitin to APC substrates in vivo. In Saccharomyces cerevisiae this RING-H2 finger protein defines the minimal ubiquitin ligase activity of the APC, and the integrity of the RING-H2 finger is essential for budding yeast cell viability.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130390333   1 MRIELTEVHGVFNWVWDIPKnedrldesmadedEDVCGICRASYHAPCPNCRYPGESCAIVLGRCGHNFHVHCISRWVDT 80
Cdd:pfam12861   1 MKVKIKEWNAVATWLWDVPS-------------DDVCGICRVSFDGTCPDCKFPGDDCPLVWGKCSHNFHMHCILKWLHT 67

                          90
                  ....*....|....*.
gi 2130390333  81 PTSKGLCPMCRQKFQL 96
Cdd:pfam12861  68 ETSKGLCPMCRQTFKF 83

Component of SCF ubiquitin ligase and anaphase-promoting complex [Posttranslational modification, protein turnover, chaperones / Cell division and chromosome partitioning];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130390333   1 MRIELTEVHGVFNWVWDIPKnedrldesmadedeDVCGICRASYHAPCPNCRY---PGESCAIVLGRCGHNFHVHCISRW 77
Cdd:COG5194     1 MKVKIKKWHAVALWSWDIPI--------------DVCAICRNHIMGTCPECQFgmtPGDECPVVWGVCNHAFHDHCIYRW 66

                          90
                  ....*....|....*....
gi 2130390333  78 VDTptsKGLCPMCRQKFQL 96
Cdd:COG5194    67 LDT---KGVCPLDRQTWVL 82

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 2130390333   48 CPNCRYPGESCAIVLGrCGHNFHVHCISRWVDTPTSKglCPMC 90
Cdd:smart00184   1 CPICLEEYLKDPVILP-CGHTFCRSCIRKWLESGNNT--CPIC 40

Anaphase-promoting complex subunit 11 RING-H2 finger; Apc11 is one of the subunits of the anaphase-promoting complex or cyclosome. The APC subunits are cullin family proteins with ubiquitin ligase activity. Polyubiquitination marks proteins for degradation by the 26S proteasome and is carried out by a cascade of enzymes that includes ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). Apc11 acts as an E3 enzyme and is responsible for recruiting E2s to the APC and for mediating the subsequent transfer of ubiquitin to APC substrates in vivo. In Saccharomyces cerevisiae this RING-H2 finger protein defines the minimal ubiquitin ligase activity of the APC, and the integrity of the RING-H2 finger is essential for budding yeast cell viability.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130390333   1 MRIELTEVHGVFNWVWDIPKnedrldesmadedEDVCGICRASYHAPCPNCRYPGESCAIVLGRCGHNFHVHCISRWVDT 80
Cdd:pfam12861   1 MKVKIKEWNAVATWLWDVPS-------------DDVCGICRVSFDGTCPDCKFPGDDCPLVWGKCSHNFHMHCILKWLHT 67

                          90
                  ....*....|....*.
gi 2130390333  81 PTSKGLCPMCRQKFQL 96
Cdd:pfam12861  68 ETSKGLCPMCRQTFKF 83

Component of SCF ubiquitin ligase and anaphase-promoting complex [Posttranslational modification, protein turnover, chaperones / Cell division and chromosome partitioning];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2130390333   1 MRIELTEVHGVFNWVWDIPKnedrldesmadedeDVCGICRASYHAPCPNCRY---PGESCAIVLGRCGHNFHVHCISRW 77
Cdd:COG5194     1 MKVKIKKWHAVALWSWDIPI--------------DVCAICRNHIMGTCPECQFgmtPGDECPVVWGVCNHAFHDHCIYRW 66

                          90
                  ....*....|....*....
gi 2130390333  78 VDTptsKGLCPMCRQKFQL 96
Cdd:COG5194    67 LDT---KGVCPLDRQTWVL 82

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 2130390333  35 DVCGICRASYHAPCPNCR-----YPGESCAIVLGRCGHNFHVHCISRWVDTptsKGLCPMCRQK 93
Cdd:cd16485     1 DNCAICRNHIMDLCIECQanqasATSEECTVAWGVCNHAFHFHCISRWLKT---RQVCPLDNRE 61

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        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2130390333  34 EDVCGICRASYHapcpncrypGESCAIVLGRCGHNFHVHCISRWVDtpTSKGLCPMCRQKF 94
Cdd:cd23121     1 DDCCAICLSDFN---------SDEKLRQLPKCGHIFHHHCLDRWIR--YNKITCPLCRADL 50

RING finger, HC subclass, found in tripartite motif-containing protein 69 (TRIM69) and similar proteins; TRIM69, also known as RFP-like domain-containing protein trimless or RING finger protein 36 (RNF36), is a testis E3 ubiquitin-protein ligase that plays a specific role in apoptosis and may also play an important role in germ cell homeostasis during spermatogenesis. TRIM69 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2130390333  37 CGICRASYHAPcpncrypgescaiVLGRCGHNFHVHCISRWVDTPTSKGLCPMCRQKFQ 95
Cdd:cd16611     7 CPLCLDFFRDP-------------VMLSCGHNFCQSCITGFWELQAEDTTCPECRELCQ 52

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 2130390333  65 CGHNFHVHCISRWVdtpTSKGLCPMCRQ 92
Cdd:cd16673    21 CAHEFHIHCIDRWL---SENSTCPICRQ 45

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 2130390333  65 CGHNFHVHCISRWVDTPTSkglCPMCRQ 92
Cdd:cd16674    21 CSHEYHVHCIDRWLSENST---CPICRR 45

RING finger, H2 subclass, found in BRCA1-associated protein (BRAP2) and similar proteins; BRAP2, also known as impedes mitogenic signal propagation (IMP), RING finger protein 52, or renal carcinoma antigen NY-REN-63, is a novel cytoplasmic protein interacting with the two functional nuclear localization signal (NLS) motifs of BRCA1, a nuclear protein linked to breast cancer. It also binds to the SV40 large T antigen NLS motif and the bipartite NLS motif found in mitosin. BRAP2 serves as a cytoplasmic retention protein and plays a role in the regulation of nuclear protein transport. It contains an N-terminal RNA recognition motif (RRM), also known as RBD (RNA binding domain) or RNP (ribonucleoprotein domain), followed by a C3H2C3-type RING-H2 finger and a UBP-type zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 2130390333  48 CPNC--RYPGESCAIVLGRCGHNFHVHCISRWVDTPtskglCPMCR 91
Cdd:cd16457     3 CPVCleRMDESVSGILTILCNHSFHCSCLSKWGDSS-----CPVCR 43

RING finger, HC subclass, found in SNF2 histone-linker PHD finger RING finger helicase (SHPRH) and similar proteins; SHPRH is a yeast RAD5 homolog found in mammals. It functions as an E3 ubiquitin-protein ligase that associates with proliferating cell nuclear antigen (PCNA), RAD18, and the ubiquitin-conjugating enzyme UBC13 (E2), and suppresses genomic instability by proliferating methyl methanesulfonate (MMS)-induced PCNA polyubiquitination. SHPRH contains a SWI/SNF helicase domain that is divided into N- and C-terminal parts by an insertion of a linker histone domain (H15), a PHD-finger, and a C3HC4-type RING-HC finger involved in the poly-ubiquitination of PCNA. This subfamily also includes tripartite motif-containing protein 15 (TRIM15). TRIM15, also known as RING finger protein 93 (RNF93), zinc finger protein 178 (ZNF178), or zinc finger protein B7 (ZNFB7), is a focal adhesion protein that regulates focal adhesion disassembly. It localizes to focal contacts in a myosin-II-independent manner by an interaction between its coiled-coil domain and the LD2 motif of paxillin. TRIM15 can also associate with coronin 1B, cortactin, filamin binding LIM protein1, and vasodilator-stimulated phosphoprotein, which are involved in actin cytoskeleton dynamics. As an additional component of the integrin adhesome, it regulates focal adhesion turnover and cell migration. TRIM15 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2130390333  47 PCPNCRYPGESCAIVLGrCGHNFHVHCISRWVDTPT----SKGLCPMCRQKF 94
Cdd:cd16569     3 PCPICARPLGKQWSVLP-CGHCFCLECIAILIDQYAqsrrRSLKCPICRETT 53

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 2130390333   48 CPNCRYPGESCAIVLGrCGHNFHVHCISRWVDTPTSKglCPMC 90
Cdd:smart00184   1 CPICLEEYLKDPVILP-CGHTFCRSCIRKWLESGNNT--CPIC 40

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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2130390333  31 DEDEDVCGICRASYhapcpncrypGESCAIVLGRCGHNFHVHCISRWVDTPTSkglCPMCRQKFQL 96
Cdd:cd23122     8 DACEDACSICLESF----------CEADPATVTSCKHEYHLQCILEWSQRSKE---CPMCWQALSL 60

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 2130390333  52 RYPGESCAIVLG-----------RCGHNFHVHCISRWVDTPTSKglCPMCRQK 93
Cdd:cd16473     1 MLECEECAICLEnyqngdllrglPCGHVFHQNCIDVWLERDNHC--CPVCRWP 51

Modified RING finger, C3HGC3-type, found in RING finger and WD repeat domain-containing protein 3 (RFWD3) and similar proteins; RFWD3, also known as RING finger protein 201 (RNF201) or FLJ10520, is an E3 ubiquitin-protein ligase that forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and acts as a positive regulator of p53 stability in response to DNA damage. It is phosphorylated by checkpoint kinase ATM/ATR and the phosphorylation mutant fails to stimulate p53 ubiquitination. RFWD3 also functions as a novel replication protein A (RPA)-associated protein involved in DNA replication checkpoint control. RFWD3 contains an N-terminal SQ-rich region followed by a RING finger domain that exhibits robust E3 ubiquitin ligase activity toward p53, a coiled-coil domain and three WD40 repeats in the C-terminus, the latter two of which may be responsible for protein-protein interaction. The RING finger in this family is a modified C3HGC3-type RING finger, but not a canonical C3H2C3-type RING-H2 finger or C3HC4-type RING-HC finger.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 2130390333  64 RCGHNFHVHCISRWVDtpTSKGLCPMCRQKFQ 95
Cdd:cd16450    24 KCGHLFGYSCIEKWLK--GKGKKCPQCNKKAK 53

RING finger, HC subclass, found in tripartite motif-containing proteins, TRIM7, TRIM11 and TRIM27, and similar proteins; TRIM7, TRIM11 and TRIM27, closely related tripartite motif-containing proteins, belong to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM7, also known as glycogenin-interacting protein (GNIP) or RING finger protein 90 (RNF90), is an E3 ubiquitin-protein ligase that mediates c-Jun/AP-1 activation by Ras signalling. Its phosphorylation and activation by MSK1 in response to direct activation by the Ras-Raf-MEK-ERK pathway can stimulate TRIM7 E3 ubiquitin ligase activity in mediating Lys63-linked ubiquitination of the AP-1 coactivator RACO-1, leading to RACO-1 protein stabilization. Moreover, TRIM7 binds and activates glycogenin, the self-glucosylating initiator of glycogen biosynthesis. TRIM11, also known as protein BIA1, or RING finger protein 92 (RNF92), is an E3 ubiquitin-protein ligase involved in the development of the central nervous system. It is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. TRIM11 acts as a potential therapeutic target for congenital central hypoventilation syndrome (CCHS) by mediating the degradation of CCHS-associated polyalanine-expanded Phox2b. TRIM11 modulates the function of neurogenic transcription factor Pax6 through the ubiquitin-proteosome system, and thus plays an essential role for Pax6-dependent neurogenesis. It also binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105), humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults, and further regulates ARC105 function in transforming growth factor beta (TGFbeta) signaling. Moreover, TRIM11 negatively regulates retinoic acid-inducible gene-I (RIG-I)-mediated interferon-beta (IFNbeta) production and antiviral activity by targeting TANK-binding kinase-1 (TBK1). It may contribute to the endogenous restriction of retroviruses in cells. It enhances N-tropic murine leukemia virus (N-MLV) entry by interfering with Ref1 restriction. It also suppresses the early steps of human immunodeficiency virus HIV-1 transduction, resulting in decreased reverse transcripts. TRIM27, also known as RING finger protein 76 (RNF76), RET finger protein (RFP), or zinc finger protein RFP, is a nuclear E3 ubiquitin-protein ligase that is highly expressed in testis and in various tumor cell lines. Expression of TRIM27 is associated with prognosis of colon and endometrial cancers. TRIM27 was first identified as a fusion partner of the RET receptor tyrosine kinase. It functions as a transcriptional repressor and associates with several proteins involved in transcriptional activity, such as enhancer of polycomb 1 (Epc1), a member of the Polycomb group proteins, and Mi-2beta, a main component of the nucleosome remodeling and deacetylase (NuRD) complex, and the cell cycle regulator retinoblastoma protein (RB1). It also interacts with HDAC1, leading to downregulation of thioredoxin binding protein 2 (TBP-2), which inhibits the function of thioredoxin. Moreover, TRIM27 mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy. In addition, it inhibits muscle differentiation by modulating serum response factor (SRF) and Epc1. TRIM27 promotes a non-canonical polyubiquitination of PTEN, a lipid phosphatase that catalyzes PtdIns(3,4,5)P3 (PIP3) to PtdIns(4,5)P2 (PIP2). It is an IKKepsilon-interacting protein that regulates IkappaB kinase (IKK) function and negatively regulates signaling involved in the antiviral response and inflammation. TRIM27 also forms a protein complex with MBD4 or MBD2 or MBD3, and thus plays an important role in the enhancement of transcriptional repression through MBD proteins in tumorigenesis, spermatogenesis, and embryogenesis. It is a component of an estrogen receptor 1 (ESR1) regulatory complex that is involved in estrogen receptor-mediated transcription in MCF-7 cells.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 2130390333  65 CGHNFHVHCISRWVDTPTSKGLCPMCRQKFQL 96
Cdd:cd16594    23 CGHSFCRACIARCWEEPETSASCPQCRETCPQ 54

RING finger, H2 subclass, found in Tetratricopeptide repeat protein 3 (TTC3) and similar proteins; TTC3, also known as protein DCRR1, TPR repeat protein D, TPR repeat protein 3, or RING finger protein 105 (RNF105), is an E3 ubiquitin-protein ligase encoded by a gene within the Down syndrome (DS) critical region on chromosome 21. It affects differentiation and Golgi compactness in neurons through specific actin-regulating pathways. It inhibits the neuronal-like differentiation of pheocromocytoma cells by activating RhoA and by binding to Citron proteins. TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus. It contains four N-terminal TPR motifs, a potential coiled-coil region and a Citron binding region in the central part, and a C-terminal C3H2C2-type RING-H2 finger.

                          10        20
                  ....*....|....*....|....*....
gi 2130390333  65 CGHNFHVHCISRWVDTptsKGLCPMCRQK 93
Cdd:cd16481    19 CGHIFHKECIKQWLKE---QSTCPTCRVH 44

RING finger, H2 subclass, found in Arabidopsis thaliana protein ABA INSENSITIVE RING PROTEIN 1 (AIRP1) and similar proteins; This subfamily includes Arabidopsis thaliana AIRP1 and RING-H2 finger B1a (RHB1A). AIRP1, also known as RING-type E3 ubiquitin transferase AIRP1, possesses E3 ubiquitin-protein ligase activity in vitro when associated with the E2 enzyme UBC8. It plays combinatory roles with AIRP2 in the positive regulation of the abscisic acid-mediated drought stress response. RHB1A is a probable E3 ubiquitin-protein ligase. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

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                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2130390333  33 DEDVCGICRASYHAPCPNcrypgescaiVLGRCGHNFHVHCISRWVDTPTSkglCPMC 90
Cdd:cd23116     1 DEDVCPTCLEGYTEENPK----------LLTKCGHHFHLACIYEWMERSER---CPVC 45

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.

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gi 2130390333  35 DVCGICRASYHapcpncryPGESCAIVLgrCGHNFHVHCISRWVDtptSKGLCPMC 90
Cdd:cd16469     1 DTCAVCLEEFK--------LKEELGVCP--CGHAFHTKCLKKWLE---VRNSCPIC 43

RING-CH finger, H2 subclass (C4HC3-type), found in E3 ubiquitin-protein ligase listerin and similar proteins; Listerin, also known as RING finger protein 160 or zinc finger protein 294, is the mammalian homolog of yeast Ltn1. It is widely expressed in all tissues, but motor and sensory neurons and neuronal processes in the brainstem and spinal cord are primarily affected in the mutant. Listerin is required for embryonic development and plays an important role in neurodegeneration. It also functions as a critical E3 ligase involving quality control of nonstop proteins. It mediates ubiquitylation of aberrant proteins that become stalled on ribosomes during translation. Ltn1 works with several cofactors to form a large ribosomal subunit-associated quality control complex (RQC), which mediates the ubiquitylation and extraction of ribosome-stalled nascent polypeptide chains for proteasomal degradation. It appears to first associate with nascent chain-stalled 60S subunits together with two proteins of unknown function, Tae2 and Rqc1. Listerin contains a long stretch of HEAT (Huntingtin, Elongation factor 3, PR65/A subunit of protein phosphatase 2A, and TOR) or ARM (Armadillo) repeats in the N terminus and middle region, and a catalytic RING-CH finger, also known as vRING or RINGv, with an unusual arrangement of zinc-coordinating residues in the C-terminus . Its cysteines and histidines are arranged in the sequence as C4HC3-type, rather than the C3H2C3-type in canonical RING-H2 finger.

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gi 2130390333  37 CGICRASYHAPcpNCRYPGESCAIvlgrCGHNFHVHCISRWVDTpTSKGLCPMCR 91
Cdd:cd16491     3 CPICYSVIHGS--NHSLPKLKCKT----CKNKFHSACLYKWFRS-SNKSTCPLCR 50

RING finger, H2 subclass, found in ubiquitin-protein ligase E3-alpha-2 (UBR2) and similar proteins; UBR2, also known as N-recognin-2 or E3alpha-II, is an E3 ubiquitin-protein ligase that plays an important role in maintaining genome integrity and in homologous recombination repair. It regulates the level of the transcription factor Rpn4 (also known as Son1 and Ufd5) through ubiquitylation. The ubiquitin-conjugating enzyme Rad6, another binding partner of URB2, and an additional factor Mub1, are required for the ubiquitin-dependent degradation of Rpn4. UBR2 associates with Mub1 to form a Mub1/Ubr2 complex that regulates the conserved Dsn1 kinetochore protein levels, which is a part of a quality control system that monitors kinetochore integrity, thus ensuring genomic stability. As the recognition component of a major cellular proteolytic system, UBR2 is associated with chromatin and controls chromatin dynamics and gene expression in both spermatocytes and somatic cells. UBR2 also mediates transcriptional silencing during spermatogenesis via histone ubiquitination. It functions as a scaffold E3 promoting HR6B/UbcH2-dependent ubiquitylation of H2A and H2B, but not H3 and H4. It also binds to Tex19.1, also known as Tex19, a germ cell-specific protein, and metabolically stabilizes it during spermatogenesis. Furthermore, UBR2 is involved in skeletal muscle (SKM) atrophy. Its expression can be modulated by the mouse ether-a-gogo-related gene 1a (MERG1a) potassium channel. In addition, UBR2 up-regulation in cachectic muscle is mediated by the p38beta-CCAAT/enhancer binding protein (C/EBP)-beta signaling pathway responsible for the bulk of tumor-induced muscle proteolysis. UBR2 contains an N-terminal ubiquitin-recognin (UBR) box involved in binding type-1 (basic) N-end rule substrate, an N-domain (also known as ClpS domain) required for type-2 (bulky hydrophobic) N-end rule substrate recognition, a C3H2C3-type RING-H2 finger, and a C-terminal UBR-specific autoinhibitory (UAIN) domain.

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gi 2130390333  49 PNCRYPGESCAIVLGRCGHNFHVHCISRWVDTPTSK 84
Cdd:cd16686    46 PLFMHPDLSCGTHTGSCGHIMHAHCWQRYFDAVQAK 81

RING finger, HC subclass, found in RING finger protein 185 (RNF185) and similar proteins; RNF185 is an E3 ubiquitin-protein ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR). It controls the degradation of CFTR and CFTR F508del allele in a RING- and proteasome-dependent manner, but does not control that of other classical ERAD model substrates. It also negatively regulates osteogenic differentiation by targeting dishevelled2 (Dvl2), a key mediator of the Wnt signaling pathway, for degradation. Moreover, RNF185 regulates selective mitochondrial autophagy through interaction with the Bcl-2 family protein BNIP1. It also plays an important role in cell adhesion and migration through the modulation of cell migration by ubiquitinating paxillin. RNF185 contains a C3HC4-type RING-HC finger.

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gi 2130390333  61 VLGRCGHNFHVHCISRWVDTPTSKGLCPMCR 91
Cdd:cd16744    14 VVSLCGHLFCWPCLHQWLETRPNRQVCPVCK 44

RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

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gi 2130390333  37 CGICRASYHAPCPncrypgescaIVLGRCGHNFHVHCISRWVDtpTSKGLCPMC 90
Cdd:cd00162     1 CPICREEMNDRRP----------VVLLSCGHTFSRSAIARWLE--GSKQKCPFC 42

RING finger, HC subclass, found in peroxin-10 (PEX10) and similar proteins; PEX10, also known as peroxisome biogenesis factor 10, peroxisomal biogenesis factor 10, peroxisome assembly protein 10, or RING finger protein 69 (RNF69), is an integral peroxisomal membrane protein with two transmembrane regions and a C3HC4-type RING-HC finger within its cytoplasmically exposed C-terminus. It plays an essential role in peroxisome assembly, import of target substrates, and recycling or degradation of protein complexes and amino acids. It is an essential component of the spinal locomotor circuit, and thus its mutations may be involved in peroxisomal biogenesis disorders (PBD). Mutations in human PEX10 also result in autosomal recessive ataxia. Moreover, PEX10 functions as an E3-ubiquitin ligase with an E2, UBCH5C. It mono- or poly-ubiquitinates PEX5, a key player in peroxisomal matrix protein import, in a UBC4-dependent manner, to control PEX5 receptor recycling or degradation. It also links the E2 ubiquitin conjugating enzyme PEX4 to the protein import machinery of the peroxisome.

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gi 2130390333  65 CGHNFHVHCISRWVdtpTSKGLCPMCRQKFQL 96
Cdd:cd16527    18 CGHLFCWSCITEWC---NEKPECPLCREPFQP 46

RING finger, HC subclass, found in RING finger protein 8 (RNF8) and similar proteins; RNF8 is a telomere-associated E3 ubiquitin-protein ligase that plays an important role in DNA double-strand break (DSB) repair via histone ubiquitination. It is localized in the nucleus and interacts with class III E2s (UBE2E2, UbcH6, and UBE2E3), but not with other E2s (UbcH5, UbcH7, UbcH10, hCdc34, and hBendless). It recruits UBC13 for lysine 63-based self polyubiquitylation. Its deficiency causes neuronal pathology and cognitive decline, and its loss results in neuron degeneration. RNF8, together with RNF168, catalyzes a series of ubiquitylation events on substrates such as H2A and H2AX, with the H2AK13/15 ubiquitylation being particularly important for recruitment of repair factors p53-binding protein 1 (53BP1) or the RAP80-BRCA1 complex to sites of DSBs. RNF8 mediates the ubiquitination of gammaH2AX, and recruits 53BP1 and BRCA1 to DNA damage sites which promotes DNA damage response (DDR) and inhibits chromosomal instability. Moreover, RNF8 interacts with retinoid X receptor alpha (RXR alpha) and enhances its transcription-stimulating activity. It also regulates the rate of exit from mitosis and cytokinesis. RNF8 contains an N-terminal forkhead-associated (FHA) domain and a C-terminal C3HC4-type RING-HC finger.

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gi 2130390333  65 CGHNFHVHCISRWVDTptsKGLCPMCRQKFQ 95
Cdd:cd16535    19 CSHSFCSYCITEWMKR---KKECPICRKPIT 46