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
                ....*....|....*....|....*....|....*....|....*....|...
gi 17561342 141 TCEICACKFEGETMDQTPRVL-GCGHTMCMGCVQKIVGQ--GYIKCPFCRIVT 190
Cdd:cd23124   3 ECGICQQEYSADDPLLIPRILtECGHTICTNCAGTILGQssGSIFCPFDRIVT 55

Modified RING finger, HC subclass (C3HC3D-type), found in Caenorhabditis elegans putative GTP-binding protein trim-23 homolog (arc-1) and similar proteins; arc-1, also called RING-type E3 ubiquitin transferase arc-1, is an E3 ubiquitin-protein ligase that mediates E2-dependent protein ubiquitination. arc-1 contains a modified C3HC3D-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 17561342 141 TCEICACKFEGETMDQTPRVL-GCGHTMCMGCVQKIVGQ--GYIKCPFCRIVT 190
Cdd:cd23124   3 ECGICQQEYSADDPLLIPRILtECGHTICTNCAGTILGQssGSIFCPFDRIVT 55

Ring finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 17561342   141 TCEICACKFEGetmDQTPRVLGCGHTMCMGCVQKIVGQGYiKCPFCR 187
Cdd:pfam13639   2 ECPICLEEFEE---GDKVVVLPCGHHFHRECLDKWLRSSN-TCPLCR 44

MAEBL; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17561342     7 RHADQRKNGAQLRAEEEANKVK---LRLTAENEKLKSEVEKLKKDHEELSRVTLKVNTEFTIQESHMARLLRENMSLKEQ 83
Cdd:PTZ00121 1641 KEAEEKKKAEELKKAEEENKIKaaeEAKKAEEDKKKAEEAKKAEEDEKKAAEALKKEAEEAKKAEELKKKEAEEKKKAEE 1720

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 17561342    84 LNDFSFKLRFR-DDMSRVEEQVKK---EQGVTDGYRRRVNQLTEFHVKSQEEQRGE 135
Cdd:PTZ00121 1721 LKKAEEENKIKaEEAKKEAEEDKKkaeEAKKDEEEKKKIAHLKKEEEKKAEEIRKE 1776

Modified RING finger, HC subclass (C3HC3D-type), found in Caenorhabditis elegans putative GTP-binding protein trim-23 homolog (arc-1) and similar proteins; arc-1, also called RING-type E3 ubiquitin transferase arc-1, is an E3 ubiquitin-protein ligase that mediates E2-dependent protein ubiquitination. arc-1 contains a modified C3HC3D-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 17561342 141 TCEICACKFEGETMDQTPRVL-GCGHTMCMGCVQKIVGQ--GYIKCPFCRIVT 190
Cdd:cd23124   3 ECGICQQEYSADDPLLIPRILtECGHTICTNCAGTILGQssGSIFCPFDRIVT 55

RING finger, HC subclass, found in tripartite motif-containing protein 32 (TRIM32) and similar proteins; TRIM32, also known as 72 kDa Tat-interacting protein, zinc finger protein HT2A, or BBS11, is an E3 ubiquitin-protein ligase that promotes degradation of several targets, including actin, PIASgamma, Abl interactor 2, dysbindin, X-linked inhibitor of apoptosis (XIAP), p73 transcription factor, thin filaments and Z-bands during fasting. It plays important roles in neuronal differentiation of neural progenitor cells, as well as in controlling cell fate in skeletal muscle progenitor cells. It reduces PI3K-Akt-FoxO signaling in muscle atrophy by promoting plakoglobin-PI3K dissociation. It also functions as a pluripotency-reprogramming roadblock that facilitates cellular transition towards differentiation by modulating the levels of Oct4 and cMyc. Moreover, TRIM32 is an intrinsic influenza A virus (IAV) restriction factor which senses and targets the polymerase basic protein 1 (PB1) for ubiquitination and protein degradation. It also plays a significant role in mediating the biological activity of the HIV-1 Tat protein in vivo, binds specifically to the activation domain of HIV-1 Tat, and can also interact with the HIV-2 and EIAV Tat proteins in vivo. Furthermore, TRIM32 regulates myoblast proliferation by controlling turnover of NDRG2 (N-myc downstream-regulated gene). It negatively regulates tumor suppressor p53 to promote tumorigenesis. It also facilitates degradation of MYCN on spindle poles and induces asymmetric cell division in human neuroblastoma cells. In addition, TRIM32 plays important roles in regulation of hyperactivities and positively regulates the development of anxiety and depression disorders induced by chronic stress. It also plays a role in regeneration by affecting satellite cell cycle progression via modulation of the SUMO ligase PIASy (PIAS4). Defects in TRIM32 leads to limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and Bardet-Biedl syndrome. TRIM32 belongs to the C-VII subclass of the TRIM (tripartite motif)-NHL family that is 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 domain, as well as a NHL (named after proteins NCL-1, HT2A and Lin-41 that contain repeats folded into a six-bladed beta propeller) repeat domain positioned C-terminal to the RBCC domain. The NHL domain mediates the interaction with Argonaute proteins and consequently allows TRIM32 to modulate the activity of certain miRNAs.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 17561342 141 TCEICACKFEGETMdqTPRVLGCGHTMCMGCVQKIV---GQGYIKCPFCRIV 189
Cdd:cd16587   2 ECPICLESFDEGQL--RPKLLHCGHTICEQCLEKLLaslSINGVRCPFCRKV 51

HC subclass of RING (RING-HC) finger and its variants; 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 a different Cys/His pattern. Some lack a single Cys or His residue at typical Zn ligand positions, especially, the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can chelate Zn in a RING finger as well. This family corresponds to the HC subclass of RING (RING-HC) fingers that are characterized by containing C3HC4-type canonical RING-HC fingers or noncanonical RING-HC finger variants, including C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type modified RING-HC fingers. The canonical RING-HC finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-HC fingers can be found in 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 enables efficient transfer of ubiquitin from E2 to the substrates.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 17561342 141 TCEICACKFEgetmdqTPRVLGCGHTMCMGCVQKIVGQGYIKCPFC 186
Cdd:cd16449   2 ECPICLERLK------DPVLLPCGHVFCRECIRRLLESGSIKCPIC 41

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 17561342 141 TCEICACKFEGETMdqtprVLGCGHTMCMGCVQKIVGQGY------IKCPFCRIVT 190
Cdd:cd16569   3 PCPICARPLGKQWS-----VLPCGHCFCLECIAILIDQYAqsrrrsLKCPICRETT 53

RING finger, HC subclass, found in RING finger protein RNF183, RNF223, RNF225 and similar proteins; RNF183 is an E3 ubiquitin-protein ligase that is upregulated during intestinal inflammation and is negatively regulated by miR-7. It promotes intestinal inflammation by increasing the ubiquitination and degradation of inhibitor of kappa B, thereby resulting in secondary activation of the Nuclear factor-kappaB (NF-kB) pathway. The interaction between RNF183-mediated ubiquitination and miRNA may be an important novel epigenetic mechanism in the pathogenesis of inflammatory bowel disease (IBD). The biological function of RNF223 and RNF225 remains unclear. Members of this family contain an N-terminal C3HC4-type RING-HC finger.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 17561342 142 CEICACKFEGetMDQTPRVLGCGHTMCMGCVQKIV-----GQGYIKCPFCRIVTKIG 193
Cdd:cd16556   3 CSICFSSYDN--TFKTPKLLDCGHTFCLECLARLSlasppQAERVPCPLCRQPTVLP 57

RING finger, HC subclass, found in tripartite motif-containing protein 59 (TRIM59) and similar proteins; TRIM59, also known as RING finger protein 104 (RNF104) or tumor suppressor TSBF-1, is a putative E3 ubiquitin-protein ligase that functions as a novel multiple cancer biomarker for immunohistochemical detection of early tumorigenesis. It is upregulated in gastric cancer and promotes gastric carcinogenesis by interacting with and targeting the P53 tumor suppressor for its ubiquitination and degradation. It also acts as a novel accessory molecule involved in cytotoxicity of BCG-activated macrophages (BAM). Moreover, TRIM59 may serve as a multifunctional regulator for innate immune signaling pathways. It interacts with ECSIT and negatively regulates nuclear factor-kappaB (NF- kappa B) and interferon regulatory factor (IRF)-3/7-mediated signal pathways. TRIM59 belongs to the C-V subclass of the TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domain, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region. In addition, TRIM59 contains a C-terminal transmembrane domain.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 17561342 141 TCEICACKFEgetmdqTPRVLGCGHTMCMGCVQKIV---GQGYI--------KCPFCR 187
Cdd:cd16763   5 TCSVCYSLFE------DPRVLPCSHTFCRNCLENILqvsGNFSIwrplrpplKCPNCR 56

Zinc finger, C3HC4 type (RING finger); The C3HC4 type zinc-finger (RING finger) is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C where X is any amino acid. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 17561342   142 CEICackfeGETMDQTPRVLGCGHTMCMGCVQKIVGQGYIKCPFC 186
Cdd:pfam00097   1 CPIC-----LEEPKDPVTLLPCGHLFCSKCIRSWLESGNVTCPLC 40

RING-type zinc-finger; This zinc-finger is a typical RING-type of plant ubiquitin ligases.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 17561342   142 CEICACKFegetmdqTPRVLGCGHTMCMGCV--QKIVGQGYIKCP 184
Cdd:pfam13445   1 CPICLELF-------TDPVLPCGHTFCRECLeeMSQKKGGKFKCP 38

Modified RING finger, HC subclass (C3HC3D-type), found in Roquin-1, Roquin-2, and similar proteins; The ROQUIN family includes Roquin-1, Roquin-2, and similar proteins, which localize to the cytoplasm and upon stress, are concentrated in stress granules. They may play essential roles in preventing T-cell-mediated autoimmune disease and in microRNA-mediated repression of inducible costimulator (Icos) mRNA. They function as E3 ubiquitin ligases consisting of an N-terminal modified C3HC3D-type RING-HC finger with a potential E3 activity, a highly conserved ROQ domain required for RNA binding and localization to stress granules, and a CCCH-type zinc finger involved in RNA recognition.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 17561342 141 TCEICACKFEGETmdQTPRVLGCGHTMCMGCVQKIVGQgyiKCPF 185
Cdd:cd16638   3 SCPVCTNEFDGTQ--RKPISLGCGHTVCKTCLSKLHRK---QCPF 42

RING finger, HC subclass, found in SH3 domain-containing RING finger protein 1 (SH3RF1) and similar proteins; SH3RF1, also known as plenty of SH3s (POSH), RING finger protein 142 (RNF142), or SH3 multiple domains protein 2 (SH3MD2), is a trans-Golgi network-associated pro-apoptotic scaffold protein with E3 ubiquitin-protein ligase activity. It also plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and c-Jun N-terminal kinase (JNK) mediated apoptosis, linking Rac1 to downstream components. SH3RF1 also enhances the ubiquitination of ROMK1 potassium channel resulting in its increased endocytosis. Moreover, SH3RF1 assembles an inhibitory complex with the actomyosin regulatory protein Shroom3, which links to the actin-myosin network to regulate neuronal process outgrowth. It also forms a complex with apoptosis-linked gene-2 (ALG-2) and ALG-2-interacting protein (ALIX/AIP1) in a calcium-dependent manner to play a role in the regulation of the JNK pathway. Furthermore, direct interaction of SH3RF1 and another molecular scaffold JNK-interacting protein (JIP) is required for apoptotic activation of JNKs. Interaction of SH3RF1 and E3 ubiquitin-protein isopeptide ligases, Siah proteins, further promotes JNK activation and apoptosis. In addition, SH3RF1 binds to and degrades TAK1, a crucial activator of both the JNK and the Relish signaling pathways. SH3RF1 contains an N-terminal C3HC4-type RING-HC finger responsible for the E3 ligase activity and four Src Homology 3 (SH3) domains, which are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 17561342 142 CEICAckfegETMDQTPRVLGCGHTMCMGCVQKIVG-QGYIKCPFCR 187
Cdd:cd16748   5 CPVCL-----ERLDATAKVLPCQHTFCRRCLLGIVGsRSELRCPECR 46

RING finger, HC subclass, found in Casitas B-lineage lymphoma (Cbl) proteins; The Cbl adaptor protein family contains a small class of RING-type E3 ubiquitin ligases with oncogenic activity, which is represented by three mammalian members, c-Cbl, Cbl-b and Cbl-c, as well as two invertebrate Cbl-family proteins, D-Cbl in Drosophila and Sli-1 in C. elegans. Cbl proteins function as potent negative regulators of various signaling cascades in a wide range of cell types. They play roles in ubiquitinating activated tyrosine kinases and targeting them for degradation. D-Cbl associates with the Drosophila epidermal growth factor receptor (EGFR) and overexpression of D-Cbl in the eye of Drosophila embryos inhibits EGFR-dependent photoreceptor cell development. Sli-1 is a negative regulator of the Let-23 receptor tyrosine kinase, an EGFR homolog, in vulva development. Cbl proteins in this subfamily consist of a highly conserved N-terminal half that includes a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain) and a C3HC4-type RING-HC finger, both of which are required for Cbl-mediated downregulation of RTKs, and a divergent C-terminal region.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 17561342 142 CEICACKfegetmDQTPRVLGCGHTMCMGCVQKIVGQGYIKCPFCR 187
Cdd:cd16502   4 CKICAEN------DKDVRIEPCGHLLCTPCLTSWQDSDGQTCPFCR 43

RING finger, HC subclass, found in RING finger protein RNF224 and similar proteins; RNF224 is uncharacterized C3HC4-type RING-HC finger-containing proteins. It may function as an E3 ubiquitin-protein ligase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 17561342 142 CEICACKFEgeTMDQTPRVLGCGHTMCMGCVQK----IVGQGYIKCPFCR 187
Cdd:cd16565   3 CIICYSAYD--LSTRLPRRLYCGHTFCQACLKRldtvINEQRWIPCPQCR 50

RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 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 17561342 141 TCEICAckfegeTMDQTPRVLGCGHTMCMGCVQKIVGQ---GYIKCPFCR 187
Cdd:cd16609   5 TCSICL------GLYQDPVTLPCQHSFCRACIEDHWRQkdeGSFSCPECR 48

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-b and similar proteins; Cbl-b, also known as Casitas B-lineage lymphoma proto-oncogene b, RING finger protein 56 (RNF56), SH3-binding protein Cbl-b, or signal transduction protein Cbl-b, has been identified as a regulator of antigen-specific, T cell-intrinsic, peripheral immune tolerance, a state also known as clonal anergy. It may inhibit activation of the p85 subunit of phosphoinositide 3-kinase (PI3K), protein kinase C-theta (PKC-theta), and phospholipase C-gamma1 (PLC-gamma1) and negatively regulates T-cell receptor-induced transcription factor nuclear factor kappaB (NF-kappaB) activation. In addition, Cbl-b may target multiple signaling molecules involved in transforming growth factor (TGF)-beta-mediated transactivation pathways. Cbl-b contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, is composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline rich domain, a nuclear localization signal, a C3HC4-type RING-HC finger and an ubiquitin-associated (UBA) domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17561342 125 HVKSQEEQ------RGEPFpwRTCEICAckfegeTMDQTPRVLGCGHTMCMGCV---QKIVGQGyikCPFCRIVTKiGTT 195
Cdd:cd16709   2 HIKVTQEQyelyceMGSTF--QLCKICA------ENDKDVKIEPCGHLMCTSCLtawQESDGQG---CPFCRCEIK-GTE 69

                ..
gi 17561342 196 PL 197
Cdd:cd16709  70 PI 71

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl and similar proteins; Cbl, also known as Casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-Cbl, RING finger protein 55 (RNF55), or signal transduction protein Cbl, is a multi-domain protein that acts as a key negative regulator of various receptor and non-receptor tyrosine kinase signaling. It contains a tyrosine kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline-rich domain, a C3HC4-type RING-HC finger, and an ubiquitin-associated (UBA) domain. TKB is responsible for the interactions with many tyrosine kinases, such as the colony-stimulating factor-1 (CSF-1) receptor, Syk/ZAP-70, and Src-family of protein tyrosine kinases. The proline-rich domain can recruit proteins with a SH3 domain. Moreover, Cbl functions as an E3 ubiquitin ligase that can bind ubiquitin-conjugating enzymes (E2s) through the RING-HC finger.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17561342 125 HVKSQEEQ------RGEPFpwRTCEICAckfegeTMDQTPRVLGCGHTMCMGCV---QKIVGQGyikCPFCRIVTKiGTT 195
Cdd:cd16708   3 HIKVTQEQyelyceMGSTF--QLCKICA------ENDKDVKIEPCGHLMCTSCLtswQESEGQG---CPFCRCEIK-GTE 70

                ..
gi 17561342 196 PL 197
Cdd:cd16708  71 PI 72

Modified RING finger, HC subclass (C3HC3D-type), found in Roquin-1; Roquin-1, also known as RING finger and C3H zinc finger protein 1 (RC3H1), or RING finger protein 198 (RNF198), is a ubiquitously expressed RNA-binding protein essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. It is localized in cytoplasmic granules and binds to the 3' untranslated region (3'UTR) of inducible costimulator (Icos) mRNA to post-transcriptionally repress its expression. Roquin-1 interacts with the 3'UTR of tumor necrosis factor receptor superfamily member 4 (TNFRSF4) and tumor-necrosis factor-alpha (TNFalpha), and post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-kappaB pathway. Moreover, Roquin-1 shares functions with its paralog Roquin-2 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation. Roquin-1 contains an N-terminal modified C3HC3D-type RING-HC finger with a potential E3 ubiquitin-ligase function, a highly conserved ROQ domain required for RNA binding and localization to stress granules, and a CCCH-type zinc finger that is involved in RNA recognition, typically contacting AU-rich elements. In addition, both N- and C-terminal to the ROQ domain are combined to form a HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain that is highly likely to function as an RNA-binding domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 17561342 141 TCEICACKFEgETMdQTPRVLGCGHTMCMGCVQKIVGQGyikCPF 185
Cdd:cd16781   8 SCPICTQTFD-ETI-RKPISLGCGHTVCKMCLNKLHRKA---CPF 47

RING finger, HC subclass, found in RNA-binding protein MEX3D; MEX3D, also known as RING finger and KH domain-containing protein 1 (RKHD1), RING finger protein 193 (RNF193), or TINO, is an RNA-binding phosphoprotein that controls the stability of the transcripts coding for the anti-apoptotic protein BCL-2, and negatively regulates BCL-2 in HeLa cells. MEX3D contains two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. Like other MEX-3 family proteins, MEX3D shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 17561342 134 GEPFPWRTCEICackFEGETMdqtPRVLGCGHTM-CMGCVQKIVGQGYIKCPFCR 187
Cdd:cd16723   5 GARKSARECVVC---FESEVI---AALVPCGHNLfCMECAIRICGKSEPECPACH 53

RING finger, HC subclass, found in Arabidopsis thaliana protein KEEP ON GOING (KEG) and similar proteins; KEG, also called RING-type E3 ubiquitin transferase KEG, is a RING E3 ubiquitin-protein ligase that mediates E2-dependent protein ubiquitination. It is essential for Arabidopsis growth and development. It acts as a negative regulator of abscisic acid signaling. It is required for ABSCISIC ACID-INSENSITIVE5 (ABI5) degradation, by mediating its ubiquitination. Together with EDR1, KEG may regulate endocytic trafficking and/or the formation of signaling complexes on trans-Golgi network (TGN)/ early endosome (EE) vesicles during stress responses. KEG is a multidomain protein that includes a C3HC4-type RING-HC finger, a kinase domain, ankyrin repeats, and 12 HERC2-like (for HECT and RCC1-like) repeats.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 17561342 142 CEICACKFEGEtmDQTPRVLGCGHTMCMGCVQKIVGQGY---IKCPFCRIVTKIG 193
Cdd:cd23140   4 CSVCSEGYNED--ERVPLLLQCGHTFCKDCLSQMFIRCTdltLKCPRCRQSVLVG 56

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.

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                ....*....|....*....|....*....|....*....|....*..
gi 17561342 142 CEICACKFEGetmDQTPRVLG-CGHTMCMGCVQKIVGQGYIKCPFCR 187
Cdd:cd23121   4 CAICLSDFNS---DEKLRQLPkCGHIFHHHCLDRWIRYNKITCPLCR 47

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM9, TRIM67, and similar proteins; Tripartite motif-containing proteins TRIM9 and TRIM67 belong to the C-I subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, consisting of three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a COS (carboxyl-terminal subgroup one signature) box, a fibronectin type III (FN3) domain, and a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. TRIM9 (the human ortholog of rat Spring), also known as RING finger protein 91 (RNF91), is a brain-specific E3 ubiquitin-protein ligase collaborating with an E2 ubiquitin conjugating enzyme UBCH5b. TRIM9 plays an important role in the regulation of neuronal functions and participates in neurodegenerative disorders through its ligase activity. TRIM67, also known as TRIM9-like protein (TNL), is a protein selectively expressed in the cerebellum. It interacts with PRG-1, an important molecule in the control of hippocampal excitability dependent on presynaptic LPA2 receptor signaling, and 80K-H, also known as glucosidase II beta, a protein kinase C substrate.

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                ....*....|....*....|....*....|....*....|....*.
gi 17561342 142 CEICACKFegetmdQTPRVLGCGHTMCMGCVQKIVgqgyIKCPFCR 187
Cdd:cd16576   6 CPVCGSLF------TEPVILPCSHNLCLGCALNIQ----LTCPICH 41

Uncharacterized protein family (UPF0242) N-terminus; This region includes an N-terminal transmembrane region and a C-terminal coiled-coil.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17561342    38 LKSEVEKLKKDHEELSRvtlkvntEFTIQESHMARLLRENMSLKEQLNDFSFKL-RFRDDMsrvEEQVKKEQGVTDGYRR 116
Cdd:pfam06785  88 LEETLEELQSEEERLEE-------ELSQKEEELRRLTEENQQLQIQLQQISQDFaEFRLES---EEQLAEKQLLINEYQQ 157

                          90
                  ....*....|....*
gi 17561342   117 RVNQLTEFHVKSQEE 131
Cdd:pfam06785 158 TIEEQRSVLEKRQDQ 172

RING finger, HC subclass, found in RNA-binding proteins of the evolutionarily-conserved MEX-3 family; MEX-3 phosphoproteins are found in vertebrates. They are mediators of post-transcriptional regulation in different organisms, and have been implicated in many core biological processes, including embryonic development, epithelial homeostasis, immune responses, metabolism, and cancer. They contain two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. They shuttle between the nucleus and the cytoplasm via the CRM1-dependent export pathway. The RNA-binding protein MEX-3 from nematode Caenorhabditis elegans is the founding member of the MEX-3 family. Due to the lack of a RING-HC finger, it is not included here.

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                ....*....|....*....|....*....|....*....|....*....
gi 17561342 140 RTCEICackFEGETMdqtPRVLGCGHTM-CMGCVQKIVGQGYIKCPFCR 187
Cdd:cd16518   1 RDCVVC---FESEVV---AALVPCGHNLfCMECANRICEKSDPECPVCH 43

RING finger, HC subclass, found in RING finger protein 152 (RNF152) and similar proteins; RNF152 is a lysosome-anchored E3 ubiquitin-protein ligase involved in apoptosis. It is polyubiquitinated through K48 linkage. It negatively regulates the activation of the mTORC1 pathway by targeting RagA GTPase for K63-linked ubiquitination. It interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The ubiquitination of RagA recruits its inhibitor GATOR1, a GAP complex for Rag GTPases, to the Rag complex, thereby inactivating mTORC1 signaling. RNF152 contains an N-terminal C3HC4-type RING-HC finger and a C-terminal transmembrane domain, both of which are responsible for its E3 ligase activity.

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                ....*....|....*....|....*....|....*....|....*..
gi 17561342 142 CEICackFEGETMDQTPRVLGCGHTMCMGCVQKI-VGQGYIKCPFCR 187
Cdd:cd16548   3 CQIC---FNYYSPRRRPKLLDCKHTCCSVCLQQMrTSQKDLRCPWCR 46

Modified RING finger, HC subclass (C3HC3D-type), found in tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) and similar proteins; TRAF4, also known as cysteine-rich domain associated with RING and Traf domains protein 1, metastatic lymph node gene 62 protein (MLN 62), or RING finger protein 83 (RNF83), is a member of the TRAF protein family, which mainly function in the immune system, where they mediate signaling through tumor necrosis factor receptors (TNFRs) and interleukin-1/Toll-like receptors (IL-1/TLRs). It also plays a critical role in nervous system, as well as in carcinogenesis. TRAF4 promotes the growth and invasion of colon cancer through the Wnt/beta-catenin pathway. It contributes to the TNFalpha-induced activation of the 70 kDa ribosomal protein S6 kinase (p70s6k) signaling pathway, and activation of transforming growth factor beta (TGF-beta)-induced SMAD-dependent signaling and non-SMAD signaling in breast cancer. It also enhances osteosarcoma cell proliferation and invasion by the Akt signaling pathway. Moreover, TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration. TRAF4 contains an N-terminal domain with a modified C3HC3D-type RING-HC finger and several zinc fingers, and a C-terminal TRAF domain that comprises a coiled coil domain and a conserved TRAF-C domain.

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                ....*....|....*....|....*....|....*....|
gi 17561342 145 CACKFEGETMDQTPRVLGCGHTMCMGCVQKIVGQGYIKCP 184
Cdd:cd16641   2 LLCPLCRLPMREPVQISTCGHRFCDTCLQEFLSEGVFKCP 41