Src homology 2 (SH2) domain found in the Cbl-b TKB domain; SH2 found in the Cbl-b TKB domain. The Cbl (for Casitas B-lineage lymphoma) family of E3 ubiquitin ligases contains three members Cbl, Cbl-b and Cbl-c. The founding member Cbl was discovered first as the oncogenic protein v-Cbl, a Gag-fusion transforming protein of Cas NS-1 retrovirus, which causes pre- and pro-B lymphomas in mice. The N-terminus of the Cbl proteins is composed of a tyrosine kinase-binding (TKB) domain, also called phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. In addition, Cbl and Cbl-b contain a leucine zipper motif and a proline-rich domain in the C-terminus. The TKB domain consists of a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. Cbl-b plays a role in early hematopoietic development and is a negative regulator of T-cell receptor, B-cell receptor and high affinity immunoglobulin epsilon receptor signal transduction pathways. It also negatively regulates insulin-like growth factor 1 signaling during muscle atrophy caused by unloading and is involved in EGFR ubiquitination and internalization. Diseases associated with defects in Cbl-b include: multiple sclerosis, autoimmune diseases, including type 1 diabetes, and a craniofacial phenotype. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007 151 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 230
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 1039792007 231 FYLFPDGRNQNPDLTGL 247
Cdd:cd09920    81 FYLYPDGRLDNPDLSGA 97

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1039792007 253 QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 329
Cdd:cd16708     1 QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 77

UBA domain found in E3 ubiquitin-protein ligase Cbl and similar proteins; Cbl, also called casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-Cbl, RING finger protein 55, or signal transduction protein Cbl, is a multi-domain protein that acts as a key negative regulator of various receptor and non-receptor tyrosine kinases signaling. It contains a tyrosine kinase-binding domain (TKB), a proline-rich domain, a RING domain, and a ubiquitin-associated (UBA) domain. The 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 SH3 domain. Moreover, Cbl functions as an E3 ubiquitin ligase that can bind ubiquitin-conjugating enzymes (E2s) through RING domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1039792007 761 LSSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNILREFV 800
Cdd:cd14393     1 LSSEIENLMSQGYSYQDIQKALVIAQNNIEMAKNILREFV 40

Src homology 2 (SH2) domain found in the Cbl-b TKB domain; SH2 found in the Cbl-b TKB domain. The Cbl (for Casitas B-lineage lymphoma) family of E3 ubiquitin ligases contains three members Cbl, Cbl-b and Cbl-c. The founding member Cbl was discovered first as the oncogenic protein v-Cbl, a Gag-fusion transforming protein of Cas NS-1 retrovirus, which causes pre- and pro-B lymphomas in mice. The N-terminus of the Cbl proteins is composed of a tyrosine kinase-binding (TKB) domain, also called phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. In addition, Cbl and Cbl-b contain a leucine zipper motif and a proline-rich domain in the C-terminus. The TKB domain consists of a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. Cbl-b plays a role in early hematopoietic development and is a negative regulator of T-cell receptor, B-cell receptor and high affinity immunoglobulin epsilon receptor signal transduction pathways. It also negatively regulates insulin-like growth factor 1 signaling during muscle atrophy caused by unloading and is involved in EGFR ubiquitination and internalization. Diseases associated with defects in Cbl-b include: multiple sclerosis, autoimmune diseases, including type 1 diabetes, and a craniofacial phenotype. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007 151 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 230
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 1039792007 231 FYLFPDGRNQNPDLTGL 247
Cdd:cd09920    81 FYLYPDGRLDNPDLSGA 97

CBL proto-oncogene N-terminus, EF hand-like domain; Cbl is an adaptor protein that binds EGF receptors (or other tyrosine kinases) and SH3 domains, functioning as a negative regulator of many signaling pathways. The N-terminal domain is evolutionarily conserved, and is known to bind to phosphorylated tyrosine residues. The so called N-terminal domain is actually 3 structural domains, of which this is the central EF hand domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007  74 FRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNW 153
Cdd:pfam02761   1 FRITKSEAAEFWKKSFGKRTIVPWKEFRTALQQVHGIESGLEAMALKSTIDLTCNDHISIFEFDVFTRLFQPWSTLLRNW 80

                  ....
gi 1039792007 154 NSLA 157
Cdd:pfam02761  81 NLLA 84

CBL proto-oncogene N-terminal domain 1; Cbl is an adaptor protein that binds EGF receptors (or other tyrosine kinases) and SH3 domains, functioning as a negative regulator of many signaling pathways. The N-terminal domain is evolutionarily conserved, and is known to bind to phosphorylated tyrosine residues. Cbl_N is comprised of 3 structural domains of which this is the first - a four helix bundle.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007   1 METLGENEYFRVFMENLMKKTKQTISLFKEGKERMYEENSQPRRNLTKLSLIFSHMLAELKGIFPSGLFQ 70
Cdd:pfam02262  56 LDALGENEYLRIYLANLLAKCKQAAKLFKEGKEKMFDEGSRYRRQLTKLSLIFSHMLAELKALFPDGKFC 125

Prokaryotic RING finger family 4; RING finger family domain found sporadically in bacteria. The finger is fused to an N-terminal alpha-helical domain, ROT/Trove-like repeats and a C-terminal TerD domain. The architecture suggests a possible role in an RNA-processing complex.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1039792007 276 CKICAENDKDVKIEPCGHLMCTSCLTSWQESegqGCPFCRCEIKGTEPI 324
Cdd:pfam14447   1 CVLCGRNGTVHALIPCGHLVCRDCFDGSDFS---ACPICRRRIDADDPF 46

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007  375 RPSSPFSMAPQASL--PPVPPRLDLLQQRAPVPASTSVLGTASKAASGSLHKDKPLPIPPTLRDLPPppppdrpysvGAE 452
Cdd:PHA03247  2685 RRAARPTVGSLTSLadPPPPPPTPEPAPHALVSATPLPPGPAAARQASPALPAAPAPPAVPAGPATP----------GGP 2754

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007  453 TRPQRRPLPCTPGD-CPSRD-------KLPPVPSSRPGDSWLSRPIPKVPVATPNPGDPWNGRE-LTNRHSLPFSLPSQM 523
Cdd:PHA03247  2755 ARPARPPTTAGPPApAPPAApaagpprRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALpPAASPAGPLPPPTSA 2834

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007  524 EPRAdvPRLGSTFsLDTSMTMNSSPVAG------PESEHPKIKPSSSANAIYSLAARP--------LPMPKLPPGEQGES 589
Cdd:PHA03247  2835 QPTA--PPPPPGP-PPPSLPLGGSVAPGgdvrrrPPSRSPAAKPAAPARPPVRRLARPavsrstesFALPPDQPERPPQP 2911

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007  590 EEDTEYMTPTSRPVGVQKPEPKRPLEATQSSRACDCDQQIDSCTYEAMYNIQSQALSVAENSASGEGNLATAHTSTGPEE 669
Cdd:PHA03247  2912 QAPPPPQPQPQPPPPPQPQPPPPPPPRPQPPLAPTTDPAGAGEPSGAVPQPWLGALVPGRVAVPRFRVPQPAPSREAPAS 2991

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007  670 SENEDDGYDVPK-------------PPVPAVLARRTLSDISNASSSFGWLSLDGDPTNFNEGSQVPERPP-------KPF 729
Cdd:PHA03247  2992 STPPLTGHSLSRvsswasslalheeTDPPPVSLKQTLWPPDDTEDSDADSLFDSDSERSDLEALDPLPPEphdpfahEPD 3071

                          410
                   ....*....|....*..
gi 1039792007  730 PRRINSERKASSYQQGG 746
Cdd:PHA03247  3072 PATPEAGARESPSSQFG 3088

UBA/TS-N domain; This small domain is composed of three alpha helices. This family includes the previously defined UBA and TS-N domains. The UBA-domain (ubiquitin associated domain) is a novel sequence motif found in several proteins having connections to ubiquitin and the ubiquitination pathway. The structure of the UBA domain consists of a compact three helix bundle. This domain is found at the N terminus of EF-TS hence the name TS-N. The structure of EF-TS is known and this domain is implicated in its interaction with EF-TU. The domain has been found in non EF-TS proteins such as alpha-NAC and MJ0280.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1039792007 762 SSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNIL 796
Cdd:pfam00627   3 EEAIQRLVEMGFDREQVREALRATGNNVERAAEYL 37

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007 376 PSSPFSMAPQASLPPVPPrldLLQQRAPVPASTSVLGTASKAASGSLH--KDKPLPIPPTLRDLPPPPPPDRPYSVGAET 453
Cdd:pfam03154 294 PPQPFPLTPQSSQSQVPP---GPSPAAPGQSQQRIHTPPSQSQLQSQQppREQPLPPAPLSMPHIKPPPTTPIPQLPNPQ 370

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007 454 RPQRRPLPCTPGDCPSRDKLPPVPSSRPGDSWLSR--------PIPKVPVATPNPGDPWNGRELTNRHSLP--------- 516
Cdd:pfam03154 371 SHKHPPHLSGPSPFQMNSNLPPPPALKPLSSLSTHhppsahppPLQLMPQSQQLPPPPAQPPVLTQSQSLPppaashppt 450

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007 517 ---FSLPSQME-PRADVPRLGSTFSLDTSMTMNSSPVAGPESEHPKIKPSSSANAIYSLAARPLPMPKLPPGEQGESEED 592
Cdd:pfam03154 451 sglHQVPSQSPfPQHPFVPGGPPPITPPSGPPTSTSSAMPGIQPPSSASVSSSGPVPAAVSCPLPPVQIKEEALDEAEEP 530

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|
gi 1039792007 593 TEYMTPTSRPvgvqKPEP---KRPLEATQSSRACD-CDQQIDSCTYEAMY 638
Cdd:pfam03154 531 ESPPPPPRSP----SPEPtvvNTPSHASQSARFYKhLDRGYNSCARTDLY 576

Src homology 2 (SH2) domain found in the Cbl-b TKB domain; SH2 found in the Cbl-b TKB domain. The Cbl (for Casitas B-lineage lymphoma) family of E3 ubiquitin ligases contains three members Cbl, Cbl-b and Cbl-c. The founding member Cbl was discovered first as the oncogenic protein v-Cbl, a Gag-fusion transforming protein of Cas NS-1 retrovirus, which causes pre- and pro-B lymphomas in mice. The N-terminus of the Cbl proteins is composed of a tyrosine kinase-binding (TKB) domain, also called phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. In addition, Cbl and Cbl-b contain a leucine zipper motif and a proline-rich domain in the C-terminus. The TKB domain consists of a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. Cbl-b plays a role in early hematopoietic development and is a negative regulator of T-cell receptor, B-cell receptor and high affinity immunoglobulin epsilon receptor signal transduction pathways. It also negatively regulates insulin-like growth factor 1 signaling during muscle atrophy caused by unloading and is involved in EGFR ubiquitination and internalization. Diseases associated with defects in Cbl-b include: multiple sclerosis, autoimmune diseases, including type 1 diabetes, and a craniofacial phenotype. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007 151 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 230
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 1039792007 231 FYLFPDGRNQNPDLTGL 247
Cdd:cd09920    81 FYLYPDGRLDNPDLSGA 97

CBL proto-oncogene N-terminus, EF hand-like domain; Cbl is an adaptor protein that binds EGF receptors (or other tyrosine kinases) and SH3 domains, functioning as a negative regulator of many signaling pathways. The N-terminal domain is evolutionarily conserved, and is known to bind to phosphorylated tyrosine residues. The so called N-terminal domain is actually 3 structural domains, of which this is the central EF hand domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039792007  74 FRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNW 153
Cdd:pfam02761   1 FRITKSEAAEFWKKSFGKRTIVPWKEFRTALQQVHGIESGLEAMALKSTIDLTCNDHISIFEFDVFTRLFQPWSTLLRNW 80

                  ....
gi 1039792007 154 NSLA 157
Cdd:pfam02761  81 NLLA 84

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1039792007 254 DHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 329
Cdd:cd16709     1 DHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTAWQESDGQGCPFCRCEIKGTEPIIVDPF 76

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-c and similar proteins; Cbl-c, also known as RING finger protein 57 (RNF57), SH3-binding protein Cbl-3, SH3-binding protein Cbl-c, or signal transduction protein Cbl-c, is an E3 ubiquitin-protein ligase expressed exclusively in epithelial cells. 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 C3HC4-type RING-HC finger, and a short proline-rich region, but lacks the ubiquitin-associated (UBA) leucine zipper motif that are present in Cbl and Cbl-b. Cbl-c acts as a regulator of epidermal growth factor receptor (EGFR)-mediated signal transduction. It also suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Moreover, Cbl-c ubiquitinates and downregulates RETMEN2A and implicates Enigma (PDLIM7) as a positive regulator of RETMEN2A by blocking Cbl-mediated ubiquitination and degradation. The ubiquitin ligase activity of Cbl-c is increased via the interaction of its RING-HC finger domain with a LIM domain of the paxillin homolog, hydrogen peroxide induced construct 5 (Hic-5).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1039792007 261 EQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPI 324
Cdd:cd16710     1 EQLQLYQAMNSTFELCKICAERDKDVRIEPCGHLLCSCCLAAWQHSDSQTCPFCRCEIKGREAV 64

UBA domain found in E3 ubiquitin-protein ligase Cbl and similar proteins; Cbl, also called casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-Cbl, RING finger protein 55, or signal transduction protein Cbl, is a multi-domain protein that acts as a key negative regulator of various receptor and non-receptor tyrosine kinases signaling. It contains a tyrosine kinase-binding domain (TKB), a proline-rich domain, a RING domain, and a ubiquitin-associated (UBA) domain. The 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 SH3 domain. Moreover, Cbl functions as an E3 ubiquitin ligase that can bind ubiquitin-conjugating enzymes (E2s) through RING domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1039792007 761 LSSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNILREFV 800
Cdd:cd14393     1 LSSEIENLMSQGYSYQDIQKALVIAQNNIEMAKNILREFV 40

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
                  ....*....|....*....|....*....|....*....|..
gi 1039792007 276 CKICAENDKD---VKIEPCGHLMCTSCLTSWQESEGQGCPFC 314
Cdd:cd00162     1 CPICREEMNDrrpVVLLSCGHTFSRSAIARWLEGSKQKCPFC 42

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 1039792007 276 CKICAENDKD-VKIEPCGHLMCTSCLTSWQESEGQGCPFC 314
Cdd:pfam00097   1 CPICLEEPKDpVTLLPCGHLFCSKCIRSWLESGNVTCPLC 40

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1039792007 274 QLCKICAENDKDVKIEPCGHL-MCTSCLTSWqESEGQGCPFCRCEIKGT 321
Cdd:pfam13920   3 LLCVICLDRPRNVVLLPCGHLcLCEECAERL-LRKKKKCPICRQPIESV 50

UBA domain found in E3 ubiquitin-protein ligase Cbl-b and similar proteins; Cbl-b, also called casitas B-lineage lymphoma proto-oncogene b, RING finger protein 56, 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 called 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 proline rich domain, a nuclear localization signal, a C3HC4 zinc finger and a ubiquitin-associated (UBA) domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1039792007 761 LSSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNILREFV 800
Cdd:cd14392     2 VDAKIAKLMGEGYSFEEVKRALEIAQNNVEVARSILREFA 41

Modified RING finger, HC subclass (C3HC5-type), found in RING finger proteins, RNF26, RNF197 (CGRRF1), RNF156 (MGRN1), RNF157 and similar proteins; This subfamily corresponds to a group of RING finger proteins containing a modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain. Cell growth regulator with RING finger domain protein 1 (CGRRF1), also known as cell growth regulatory gene 19 protein (CGR19) or RING finger protein 197 (RNF197), functions as a novel biomarker to monitor endometrial sensitivity and response to insulin-sensitizing drugs, such as metformin, in the context of obesity. RNF26 is an E3 ubiquitin ligase that temporally regulates virus-triggered type I interferon induction by increasing the stability of Mediator of IRF3 activation, MITA, also known as STING, through K11-linked polyubiquitination after viral infection and promoting degradation of IRF3, another important component required for virus-triggered interferon induction. Mahogunin ring finger-1 (MGRN1), also known as RING finger protein 156 (RNF156), is a cytosolic E3 ubiquitin-protein ligase that inhibits signaling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes. It suppresses chaperone-associated misfolded protein aggregation and toxicity. RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in the brain. It is a homolog of the E3 ligase MGRN1. In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1039792007 274 QLCKICAENDKDVKIEPCGHL-MCTSCLtswQESEGQGCPFCR 315
Cdd:cd16649     1 GLCVVCLENPASVLLLPCRHLcLCEVCA---KGLRGKTCPICR 40

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1039792007 276 CKICAENDKDVKIEPCGHLMCTSCLTSWQESE--GQGCPFCRCEIKGTEPI 324
Cdd:cd16744     3 CNICLDTAKDAVVSLCGHLFCWPCLHQWLETRpnRQVCPVCKAGISRDKVI 53

Ubiquitin associated domain; Present in Rad23, SNF1-like kinases. The newly-found UBA in p62 is known to bind ubiquitin.

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1039792007  761 LSSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNIL 796
Cdd:smart00165   1 DEEKIDQLLEMGFSREEALKALRAANGNVERAAEYL 36

RING finger, HC subclass, found in RING finger protein 5 (RNF5) and similar proteins; RNF5, also known as protein G16 or Ram1, is an E3 ubiquitin-protein ligase anchored to the outer membrane of the endoplasmic reticulum (ER). It acts at early stages of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) biosynthesis and functions as a target for therapeutic modalities to antagonize mutant CFTR proteins in CF patients carrying the F508del allele. It also regulates the turnover of specific G protein-coupled receptors by ubiquitinating JNK-associated membrane protein (JAMP) and preventing proteasome recruitment. RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection through the regulation of ATG4B stability. It is also involved in the degradation of Pendrin, a transmembrane chloride/anion exchanger highly expressed in thyroid, kidney, and inner ear. RNF5 plays an important role in cell adhesion and migration. It can modulate cell migration by ubiquitinating paxillin. Furthermore, RNF5 interacts with virus-induced signaling adaptor (VISA) at mitochondria in a viral infection-dependent manner, and further targets VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection. It also negatively regulates virus-triggered signaling by targeting MITA, also known as STING, for ubiquitination and degradation at the mitochondria. In addition, RNF5 determines breast cancer response to ER stress-inducing chemotherapies through the regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2). It also has been implicated in muscle organization and in recognition and processing of misfolded proteins. RNF5 contains a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1039792007 276 CKICAENDKDVKIEPCGHLMCTSCLTSWQES--EGQGCPFCRCEI 318
Cdd:cd16743     3 CNICLETARDAVVSLCGHLFCWPCLHQWLETrpERQECPVCKAGI 47

UBA/TS-N domain; This small domain is composed of three alpha helices. This family includes the previously defined UBA and TS-N domains. The UBA-domain (ubiquitin associated domain) is a novel sequence motif found in several proteins having connections to ubiquitin and the ubiquitination pathway. The structure of the UBA domain consists of a compact three helix bundle. This domain is found at the N terminus of EF-TS hence the name TS-N. The structure of EF-TS is known and this domain is implicated in its interaction with EF-TU. The domain has been found in non EF-TS proteins such as alpha-NAC and MJ0280.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 1039792007 762 SSEIERLMSQGYSYQDIQKALVIAHNNIEMAKNIL 796
Cdd:pfam00627   3 EEAIQRLVEMGFDREQVREALRATGNNVERAAEYL 37

RING finger, HC subclass, found in RING finger protein 138 (RNF138) and similar proteins; RNF138, also known as Nemo-like kinase-associated RING finger protein (NARF) or NLK-associated RING finger protein, is an E3 ubiquitin-protein ligase that plays an important role in glioma cell proliferation, apoptosis, and cell cycle. It specifically cooperates with the E2 conjugating enzyme E2-25K (Hip-2/UbcH1), regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF), and further suppresses Wnt-beta-catenin signaling. RNF138, together with three closely related proteins: RNF114, RNF125 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1039792007 275 LCKICAENDKD-VKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEP 323
Cdd:cd16544     4 TCPVCQEVLKDpVELPPCRHIFCKACILLALRSSGARCPLCRGPVGKTER 53

RING finger, HC subclass, found in apoptosis protein c-IAP1, c-IAP2, livin, and similar proteins; The cellular inhibitor of apoptosis protein c-IAPs function as ubiquitin E3 ligases that mediate the ubiquitination of substrates involved in apoptosis, nuclear factor-kappaB (NF-kappaB) signaling, and oncogenesis. Unlike other IAPs, such as XIAP, c-IAPs exhibit minimal binding to caspases and may not play an important role in the inhibition of these proteases. c-IAP1, also known as baculoviral IAP repeat-containing protein BIRC2, IAP-2, RING finger protein 48, or TNFR2-TRAF-signaling complex protein 2, is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-kappaB signaling pathways in the cytoplasm. It can also regulate E2F1 transcription factor-mediated control of cyclin transcription in the nucleus. c-IAP2, also known as BIRC3, IAP-1, apoptosis inhibitor 2 (API2), or IAP homolog C, also influences ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-kappaB. c-IAPs contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), a caspase activation and recruitment domain (CARD) that serves as a protein interaction surface, and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. Livin, also known as baculoviral IAP repeat-containing protein 7 (BIRC7), kidney inhibitor of apoptosis protein (KIAP), melanoma inhibitor of apoptosis protein (ML-IAP), or RING finger protein 50, was identified as the melanoma IAP. It plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is regulated by the inhibition of caspase-3, -7, and -9. Its E3 ubiquitin-ligase-like activity promotes degradation of Smac/DIABLO, a critical endogenous regulator of all IAPs. Unlike other family members, mammalian livin contains a single BIR domain and a C3HC4-type RING-HC finger. The UBA domain can be detected in non-mammalian homologs of livin.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1039792007 276 CKICAENDKDVKIEPCGHLM-CTSCLTSWQEsegqgCPFCRCEIKGT 321
Cdd:cd16713    10 CKVCMDKEVSIVFIPCGHLVvCTECAPSLRK-----CPICRATIKGT 51

RING finger, HC subclass, found in RING finger protein 213 (RNF213) and similar proteins; RNF213, also known as ALK lymphoma oligomerization partner on chromosome 17 or Moyamoya steno-occlusive disease-associated AAA+ and RING finger protein (mysterin), is an intracellular soluble protein that functions as an E3 ubiquitin-protein ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell. It plays a unique role in endothelial cells for proper gene expression in response to inflammatory signals from the environment. Mutations in RNF213 may be associated with Moyamoya disease (MMD), an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. It also acts as a nuclear marker for acanthomorph phylogeny. RNF213 contains two tandem enzymatically active AAA+ ATPase modules and a C3HC4-type RING-HC finger. It can form a huge ring-shaped oligomeric complex.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1039792007 274 QLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQgCPFCRCEIK 319
Cdd:cd16561     3 QECSICLEDLNDPVKLPCDHVFCEECIRQWLPGQMS-CPLCRTELP 47

RING finger, H2 subclass, found in synoviolin and similar proteins; Synoviolin, also known as synovial apoptosis inhibitor 1 (Syvn1), Hrd1, or Der3, is an endoplasmic reticulum (ER)-anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis and plays a role in homeostasis maintenance. It also targets tumor suppressor gene p53 for proteasomal degradation, suggesting crosstalk between ER associated degradation (ERAD) and p53 mediated apoptotic pathway under ER stress. Moreover, synoviolin controls body weight and mitochondrial biogenesis through negative regulation of the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1beta. It upregulates amyloid beta production by targeting a negative regulator of gamma-secretase, Retention in endoplasmic reticulum 1 (Rer1), for degradation. It is also involved in the degradation of endogenous immature nicastrin, and affects amyloid beta-protein generation. Moreover, synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of rheumatoid arthritis (RA). It functions as an anti-apoptotic factor that is responsible for the outgrowth of synovial cells during the development of RA. It promotes inositol-requiring enzyme 1 (IRE1) ubiquitination and degradation in synovial fibroblasts with collagen-induced arthritis. Furthermore, the upregulation of synoviolin may represent a protective response against neurodegeneration in Parkinson's disease (PD). In addition, synoviolin is involved in liver fibrogenesis. Synoviolin contains a C3H2C2-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1039792007 274 QLCKICAEN-DKDVKIEPCGHLMCTSCLTSWQESEgQGCPFCR 315
Cdd:cd16479     2 NTCIICREEmTVGAKKLPCGHIFHLSCLRSWLQRQ-QTCPTCR 43

RING finger, H2 subclass, found in autocrine motility factor receptor (AMFR) and similar proteins; AMFR, also known as AMF receptor, or RING finger protein 45, or ER-protein gp78, is an internalizing cell surface glycoprotein localized in both plasma membrane caveolae and the endoplasmic reticulum (ER). It is involved in the regulation of cellular adhesion, proliferation, motility and apoptosis, as well as in the process of learning and memory. AMFR also functions as a RING finger-dependent ubiquitin protein ligase (E3) implicated in the degradation from the ER. AMFR contains an N-terminal RING-H2 finger and a C-terminal ubiquitin-associated (UBA)-like CUE domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1039792007 276 CKICAENDKDVKIEPCGHLMCTSCLTSWQEsEGQGCPFCR 315
Cdd:cd16455     3 CAICWESMQSARKLPCGHLFHNSCLRSWLE-QDTSCPTCR 41

Modified RING finger, HC subclass (C3HC5-type), found in RING finger protein 26 (RNF26) and similar proteins; RNF26 is an E3 ubiquitin ligase that temporally regulates virus-triggered type I interferon induction by increasing the stability of Mediator of IRF3 activation, MITA, also known as STING, through K11-linked polyubiquitination of MITA after viral infection, and promoting the degradation of IRF3, another important component required for virus-triggered interferon induction. Although RNF26 substrates of ubiquitination remain unclear at present, RNF26 upregulation in gastric cancer might be implicated in carcinogenesis through dysregulation of growth regulators. RNF26 contains an N-terminal leucine zipper domain and a C-terminal modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1039792007 275 LCKICAENDKDVKIEPCGHL-MCTSC----LTSWQESegQGCPFCRCEIKGT 321
Cdd:cd16788     7 KCVICQDQSKTVLILPCRHMcLCRQCanilLQQPVYR--RNCPLCRTMILQT 56

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein 1A (NEURL1A) and similar proteins; NEURL1A, also known as NEURL1, NEU, neuralized 1, or RING finger protein 67 (RNF67), is a mammalian homolog of the Drosophila neuralized (D-neu) protein. It functions as an E3 ubiquitin-protein ligase that directly interacts with and monoubiquitinates cytoplasmic polyadenylation element-binding protein 3 (CPEB3), an RNA binding protein and a translational regulator of local protein synthesis, which facilitates hippocampal plasticity and hippocampal-dependent memory storage. It also acts as a potential tumor suppressor that causes apoptosis and downregulates Notch target genes in the medulloblastoma. NEURL1A contains two neuralized homology regions (NHRs) responsible for Neural-ligand interactions and a modified C3HC5-type RING-HC finger required for ubiquitin ligase activity. The C3HC5-type RING-HC finger is distinguished from typical C3HC4-type RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1039792007 270 GSTFQLCKICAENDKDVKIEPCGHL-MCTSCLTSWQESEGQGCPFCRCEIK 319
Cdd:cd16785     1 GSWSDECTICYENAVDTVIYTCGHMcLCYACGLRLKKMLNACCPICRRAIK 51

RING finger, HC subclass, found in Saccharomyces cerevisiae POB3/SPT16 histone-associated protein 1 (ScPSH1) and similar proteins; ScPSH1 is a Cse4-specific E3 ubiquitin ligase that interacts with the kinetochore protein Pat1 and targets the degradation of budding yeast centromeric histone H3 variant, CENP-ACse4, which is essential for faithful chromosome segregation. ScPSH1 contains a C3HC4-type RING-HC finger and a DNA directed RNA polymerase domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1039792007 274 QLCKICAENDKDVKIEPCGHLMCTSCLTSWQES-EGQGCPFCRCEIKgTEP 323
Cdd:cd16568     5 QECIICHEYLYEPMVTTCGHTYCYTCLNTWFKSnRSLSCPDCRTKIT-TQP 54

RING finger, HC subclass, found in RING finger protein 123 (RNF123) and similar proteins; RNF123, also known as Kip1 ubiquitination-promoting complex protein 1 (KPC1), is an E3 ubiquitin-protein ligase that mediates ubiquitination and proteasomal processing of the nuclear factor-kappaB 1 (NF-kappaB1) precursor p105 to the p50 active subunit that restricts tumor growth. It also regulates degradation of heterochromatin protein 1alpha (HP1alpha) and 1beta (HP1beta) in lamin A/C knock-down cells. Moreover, RNF123, together with Kip1 ubiquitylation-promoting complex 2 (KPC2), forms the Kip1 ubiquitination-promoting complex (KPC), acting as a cytoplasmic ubiquitin ligase that regulates degradation of the cyclin-dependent kinase inhibitor p27 (Kip1) at the G1 phase of the cell cycle. RNF123 may also function as a clinically relevant, peripheral state marker of depression. RNF123 contains a C3HC4-type RING-HC finger at the C-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1039792007 274 QLCKICAENDKDVKIEPCGHLMCTSCLTSWQESeGQGCPFCRCEI 318
Cdd:cd16541     1 DLCPICYAHPIDAVFLPCGHKSCRSCINRHLMN-NKECFFCKATI 44

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
                  ....*....|....*....|....*....|....*....|....*..
gi 1039792007 276 CKICAENDKDVKIEPCGHLMCTSCLTSW--QESEGQGCPFCRCEIKG 320
Cdd:cd16611     7 CPLCLDFFRDPVMLSCGHNFCQSCITGFweLQAEDTTCPECRELCQY 53

RING finger, HC subclass, found in helicase-like transcription factor (HLTF) and similar proteins; HLTF, also known as DNA-binding protein/plasminogen activator inhibitor 1 regulator, HIP116, RING finger protein 80, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 3, or sucrose nonfermenting protein 2-like 3, is a yeast RAD5 homolog found in mammals. It has both E3 ubiquitin ligase and DNA helicase activities, and plays a pivotal role in the template-switching pathway of DNA damage tolerance. It is involved in Lys-63-linked poly-ubiquitination of proliferating cell nuclear antigen (PCNA) at Lys-164 and in the regulation of DNA damage tolerance. It shows double-stranded DNA translocase activity with 3'-5' polarity, thereby facilitating regression of the replication fork. HLTF contains an N-terminal HIRAN (HIP116 and RAD5 N-terminal) domain, a SWI/SNF helicase domain that is divided into N- and C-terminal parts by an insertion of a C3HC4-type RING-HC finger involved in the poly-ubiquitination of PCNA.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1039792007 276 CKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIK 319
Cdd:cd16509     6 CAICLDSLTNPVITPCAHVFCRRCICEVIQREKAKCPMCRAPLS 49

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
                  ....*....|....*....|....*....|....*....|....*
gi 1039792007 276 CKICAENDKDVKIEPCGHLMCTSCL-TSWQESEGQG--CPFCRCE 317
Cdd:cd16609     6 CSICLGLYQDPVTLPCQHSFCRACIeDHWRQKDEGSfsCPECRAP 50

RING-finger-containing E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 1039792007 276 CKICAENDKDVKIEPCGHLMCTSCL-TSWQESEGQGCPFCR 315
Cdd:COG5574   218 CFLCLEEPEVPSCTPCGHLFCLSCLlISWTKKKYEFCPLCR 258

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1039792007 268 EMGSTFQLCKICA---ENDKDVKIEPCGHLMCTSCLTSWQeSEGQGCPFCRCEIK 319
Cdd:cd16682     2 EESDTDEKCTICLsmlEDGEDVRRLPCMHLFHQLCVDQWL-AMSKKCPICRVDIE 55

RING finger, HC subclass, found in RING finger and SPRY domain-containing protein 1 (RSPRY1) and similar proteins; RSPRY1 is a hypothetical RING and SPRY domain-containing protein of unknown physiological function. Mutations in its corresponding gene RSPRY1 may associate with a distinct skeletal dysplasia syndrome. RSPRY1 contains a B30.2/SPRY domain and a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1039792007 276 CKICAENDKDVKIEPCGH----LMCTSCLTSwqesegqgCPFCRCEI 318
Cdd:cd16566     5 CTLCFDKVADTELRPCGHsgfcMECALQLET--------CPLCRQPI 43

zinc-RING finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1039792007 276 CKICAE---NDKDVKIEPCGHLMCTSCLTswQESEGQGCPFCR 315
Cdd:pfam14634   2 CNKCFKelsKTRPFYLTSCGHIFCEECLT--RLLQERQCPICK 42

RING finger, HC subclass, found in Arabidopsis thaliana protein XB3 homolog 1 (XBAT31) and similar proteins; XBAT31, also called ankyrin repeat domain and RING finger-containing protein XBAT31, or RING-type E3 ubiquitin transferase XB31, has no E3 ubiquitin-protein ligase activity observed when associated with the E2 enzyme UBC8 in vitro. XBAT31 contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1039792007 271 STFQLCKICAENDKDVKIEPCGHLMCTSCL----------TSWQESEGQGCPFCRCEI 318
Cdd:cd23144     4 SDEDVCCICFEHLCTIEIKDCGHQMCATCAlklcchnkpnPSSSPPRPPACPFCRQDI 61

RING finger, HC subclass, found in tripartite motif-containing protein 2 (TRIM2); TRIM2, also known as RING finger protein 86 (RNF86), is an E3 ubiquitin-protein ligase that ubiquitinates the neurofilament light chain, a component of the intermediate filament in axons. Loss of function of TRIM2 results in early-onset axonal neuropathy. TRIM2 also plays a role in mediating the p42/p44 MAPK-dependent ubiquitination of the cell death-promoting protein Bcl-2-interacting mediator of cell death (Bim) in rapid ischemic tolerance. TRIM2 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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1039792007 268 EMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSW--QESEGQGCPFCR 315
Cdd:cd16767     1 QIDKQFLICSICLDRYKNPKVLPCLHTFCERCLQNYipAHSLTLSCPVCR 50

RING finger, HC subclass, found in RING finger protein 14 (RNF14) and similar proteins; RNF14, also known as androgen receptor-associated protein 54 (ARA54), HFB30, or Triad2 protein, is an RBR-type E3 ubiquitin-protein ligase that is highly expressed in the testis and interacts with class III E2s (UBE2E2, UbcH6, and UBE2E3). Its differential localization may play an important role in testicular development and spermatogenesis in humans. RNF14 functions as a transcriptional regulator of mitochondrial and immune function in muscle. It is a ligand-dependent androgen receptor (AR) co-activator and may also may participate in enhancing cell cycle progression and cell proliferation via induction of cyclin D1. Moreover, RNF14 is crucial for colon cancer cell survival. It acts as a new enhancer of the Wnt-dependent transcriptional outputs that acts at the level of the T-cell factor/lymphoid enhancer factor (TCF/LEF)-beta-catenin complex. RNF14 contains an N-terminal RWD domain and a C-terminal RBR domain. The RBR domain was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been corrected as RING-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR (RING1-BRcat-Rcat) domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase function to facilitate the ubiquitination reaction. This model corresponds to the RING domain, a C3HC4-type RING-HC finger required for RBR-mediated ubiquitination.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1039792007 271 STFQLCKICAENDKDV---KIEPCGHLMCTSCLTSW---QESEGQ----GCPFCRCE 317
Cdd:cd16628     3 SKIFTCNICFLDKLGSecmYFKDCGHVYCKECLKEYfevQIRDGNvtslNCPEPKCA 59