ID MARH6_HUMAN Reviewed; 910 AA. AC O60337; A5PKZ4; B4DKJ2; B4DT33; D3DTC8; O14670; Q86X77; DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot. DT 06-FEB-2007, sequence version 2. DT 28-JUN-2023, entry version 169. DE RecName: Full=E3 ubiquitin-protein ligase MARCHF6; DE EC=2.3.2.27 {ECO:0000269|PubMed:15673284, ECO:0000269|PubMed:24449766}; DE AltName: Full=Doa10 homolog; DE AltName: Full=Membrane-associated RING finger protein 6; DE AltName: Full=Membrane-associated RING-CH protein VI; DE Short=MARCH-VI {ECO:0000303|PubMed:16373356}; DE AltName: Full=Protein TEB-4 {ECO:0000303|PubMed:15673284, ECO:0000303|PubMed:16373356, ECO:0000303|PubMed:19651899}; DE AltName: Full=RING finger protein 176; DE AltName: Full=RING-type E3 ubiquitin transferase MARCHF6 {ECO:0000305}; GN Name=MARCHF6 {ECO:0000312|HGNC:HGNC:30550}; GN Synonyms=KIAA0597, MARCH6, RNF176, TEB4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=9628581; DOI=10.1093/dnares/5.1.31; RA Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N., RA Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. IX. The RT complete sequences of 100 new cDNA clones from brain which can code for RT large proteins in vitro."; RL DNA Res. 5:31-39(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Pancreas; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 379-910 (ISOFORM 1), AND VARIANT LEU-622. RA Simmons A.D., Lovett M.L.; RT "High resolution physical and transcription maps of the Cri-du-chat RT critical region."; RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases. RN [7] RP IDENTIFICATION. RX PubMed=11641273; DOI=10.1101/gad.933301; RA Swanson R., Locher M., Hochstrasser M.; RT "A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum RT that functions in both ER-associated and Matalpha2 repressor degradation."; RL Genes Dev. 15:2660-2674(2001). RN [8] RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, TOPOLOGY, RP UBIQUITINATION, MUTAGENESIS OF CYS-9, DOMAIN, AND PATHWAY. RX PubMed=15673284; DOI=10.1042/bj20041241; RA Hassink G., Kikkert M., van Voorden S., Lee S.-J., Spaapen R., van Laar T., RA Coleman C.S., Bartee E., Frueh K., Chau V., Wiertz E.; RT "TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic RT reticulum."; RL Biochem. J. 388:647-655(2005). RN [9] RP TOPOLOGY. RX PubMed=16373356; DOI=10.1074/jbc.m512215200; RA Kreft S.G., Wang L., Hochstrasser M.; RT "Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin RT ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI)."; RL J. Biol. Chem. 281:4646-4653(2006). RN [10] RP FUNCTION AS AN E3 UBIQUITIN LIGASE FOR DIO2, AND INTERACTION WITH DIO2. RX PubMed=19651899; DOI=10.1128/mcb.01498-08; RA Zavacki A.M., Arrojo E Drigo R., Freitas B.C., Chung M., Harney J.W., RA Egri P., Wittmann G., Fekete C., Gereben B., Bianco A.C.; RT "The E3 ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine RT deiodinase."; RL Mol. Cell. Biol. 29:5339-5347(2009). RN [11] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [12] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH SQLE, MUTAGENESIS OF CYS-9, RP AND DOMAIN. RX PubMed=24449766; DOI=10.1128/mcb.01140-13; RA Zelcer N., Sharpe L.J., Loregger A., Kristiana I., Cook E.C., Phan L., RA Stevenson J., Brown A.J.; RT "The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects RT 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol RT synthesis pathway."; RL Mol. Cell. Biol. 34:1262-1270(2014). RN [13] RP INVOLVEMENT IN FAME3. RX PubMed=31664039; DOI=10.1038/s41467-019-12763-9; RG FAME consortium; RA Florian R.T., Kraft F., Leitao E., Kaya S., Klebe S., Magnin E., RA van Rootselaar A.F., Buratti J., Kuehnel T., Schroeder C., Giesselmann S., RA Tschernoster N., Altmueller J., Lamiral A., Keren B., Nava C., RA Bouteiller D., Forlani S., Jornea L., Kubica R., Ye T., Plassard D., RA Jost B., Meyer V., Deleuze J.F., Delpu Y., Avarello M.D.M., RA Vijfhuizen L.S., Rudolf G., Hirsch E., Kroes T., Reif P.S., Rosenow F., RA Ganos C., Vidailhet M., Thivard L., Mathieu A., Bourgeron T., Kurth I., RA Rafehi H., Steenpass L., Horsthemke B., LeGuern E., Klein K.M., Labauge P., RA Bennett M.F., Bahlo M., Gecz J., Corbett M.A., Tijssen M.A.J., RA van den Maagdenberg A.M.J.M., Depienne C.; RT "Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial RT Adult Myoclonic Epilepsy type 3."; RL Nat. Commun. 10:4919-4919(2019). CC -!- FUNCTION: E3 ubiquitin-protein ligase that promotes 'Lys-48'-linked CC ubiquitination of target proteins, leading to their proteasomal CC degradation (PubMed:15673284). Promotes ubiquitination of DIO2, leading CC to its degradation (PubMed:19651899). Promotes ubiquitination of SQLE, CC leading to its degradation (PubMed:24449766). E3 ubiquitin ligases CC accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of CC a thioester and then directly transfer the ubiquitin to targeted CC substrates. May cooperate with UBE2G1 (PubMed:15673284). CC {ECO:0000269|PubMed:15673284, ECO:0000269|PubMed:19651899, CC ECO:0000269|PubMed:24449766}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:15673284}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:15673284}. CC -!- SUBUNIT: Interacts with DIO2 (PubMed:19651899). Interacts with SQLE CC (PubMed:24449766). {ECO:0000269|PubMed:19651899, CC ECO:0000269|PubMed:24449766}. CC -!- INTERACTION: CC O60337; Q9UHX3: ADGRE2; NbExp=3; IntAct=EBI-2684600, EBI-11277970; CC O60337; P41220-1: RGS2; NbExp=3; IntAct=EBI-2684600, EBI-16037474; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:15673284}; Multi-pass membrane protein CC {ECO:0000269|PubMed:15673284}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O60337-4; Sequence=Displayed; CC Name=2; CC IsoId=O60337-5; Sequence=VSP_047036; CC Name=3; CC IsoId=O60337-6; Sequence=VSP_047035; CC -!- TISSUE SPECIFICITY: Present in brain (at protein level). CC {ECO:0000269|PubMed:15673284}. CC -!- DOMAIN: The RING-CH-type zinc finger domain is required for E3 ligase CC activity. {ECO:0000269|PubMed:15673284, ECO:0000269|PubMed:24449766}. CC -!- PTM: Auto-ubiquitinated, which results in proteasomal degradation. CC {ECO:0000269|PubMed:15673284}. CC -!- DISEASE: Epilepsy, familial adult myoclonic, 3 (FAME3) [MIM:613608]: A CC form of familial myoclonic epilepsy, a neurologic disorder CC characterized by cortical hand tremors, myoclonic jerks and occasional CC generalized or focal seizures with a non-progressive or very slowly CC progressive disease course. Usually, myoclonic tremor is the presenting CC symptom, characterized by tremulous finger movements and myoclonic CC jerks of the limbs increased by action and posture. In a minority of CC patients, seizures are the presenting symptom. Some patients exhibit CC mild cognitive impairment. FAME3 inheritance is autosomal dominant. CC {ECO:0000269|PubMed:31664039}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=AAB66840.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAB66840.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAA25523.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB011169; BAA25523.1; ALT_INIT; mRNA. DR EMBL; AK296585; BAG59204.1; -; mRNA. DR EMBL; AK300034; BAG61845.1; -; mRNA. DR EMBL; AC012640; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC092336; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471102; EAX08065.1; -; Genomic_DNA. DR EMBL; CH471102; EAX08066.1; -; Genomic_DNA. DR EMBL; BC046148; AAH46148.1; -; mRNA. DR EMBL; BC136461; AAI36462.1; -; mRNA. DR EMBL; BC136462; AAI36463.1; -; mRNA. DR EMBL; BC142679; AAI42680.1; -; mRNA. DR EMBL; BC142694; AAI42695.1; -; mRNA. DR EMBL; AF009301; AAB66840.1; ALT_SEQ; mRNA. DR CCDS; CCDS34135.1; -. [O60337-4] DR CCDS; CCDS59487.1; -. [O60337-5] DR CCDS; CCDS59488.1; -. [O60337-6] DR PIR; T00268; T00268. DR RefSeq; NP_001257589.1; NM_001270660.1. [O60337-5] DR RefSeq; NP_001257590.1; NM_001270661.1. [O60337-6] DR RefSeq; NP_005876.2; NM_005885.3. [O60337-4] DR AlphaFoldDB; O60337; -. DR SMR; O60337; -. DR BioGRID; 115587; 57. DR DIP; DIP-56134N; -. DR IntAct; O60337; 19. DR MINT; O60337; -. DR STRING; 9606.ENSP00000274140; -. DR iPTMnet; O60337; -. DR PhosphoSitePlus; O60337; -. DR SwissPalm; O60337; -. DR BioMuta; MARCH6; -. DR EPD; O60337; -. DR jPOST; O60337; -. DR MassIVE; O60337; -. DR MaxQB; O60337; -. DR PaxDb; O60337; -. DR PeptideAtlas; O60337; -. DR ProteomicsDB; 4463; -. DR ProteomicsDB; 49363; -. [O60337-4] DR ProteomicsDB; 5070; -. DR Antibodypedia; 22463; 175 antibodies from 29 providers. DR DNASU; 10299; -. DR Ensembl; ENST00000274140.10; ENSP00000274140.4; ENSG00000145495.16. [O60337-4] DR Ensembl; ENST00000449913.6; ENSP00000414643.2; ENSG00000145495.16. [O60337-5] DR Ensembl; ENST00000503788.5; ENSP00000425930.1; ENSG00000145495.16. [O60337-6] DR GeneID; 10299; -. DR KEGG; hsa:10299; -. DR MANE-Select; ENST00000274140.10; ENSP00000274140.4; NM_005885.4; NP_005876.2. DR UCSC; uc003jet.3; human. [O60337-4] DR AGR; HGNC:30550; -. DR CTD; 10299; -. DR DisGeNET; 10299; -. DR GeneCards; MARCHF6; -. DR HGNC; HGNC:30550; MARCHF6. DR HPA; ENSG00000145495; Low tissue specificity. DR MalaCards; MARCHF6; -. DR MIM; 613297; gene. DR MIM; 613608; phenotype. DR neXtProt; NX_O60337; -. DR OpenTargets; ENSG00000145495; -. DR Orphanet; 86814; Benign adult familial myoclonic epilepsy. DR VEuPathDB; HostDB:ENSG00000145495; -. DR eggNOG; KOG1609; Eukaryota. DR GeneTree; ENSGT00940000155171; -. DR HOGENOM; CLU_006373_1_0_1; -. DR InParanoid; O60337; -. DR OMA; WLHYSLV; -. DR OrthoDB; 1342875at2759; -. DR PhylomeDB; O60337; -. DR TreeFam; TF105777; -. DR BioCyc; MetaCyc:ENSG00000145495-MON; -. DR BRENDA; 2.3.2.27; 2681. DR PathwayCommons; O60337; -. DR Reactome; R-HSA-901032; ER Quality Control Compartment (ERQC). DR SignaLink; O60337; -. DR SIGNOR; O60337; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 10299; 39 hits in 1127 CRISPR screens. DR ChiTaRS; MARCH6; human. DR GeneWiki; MARCH6; -. DR GenomeRNAi; 10299; -. DR Pharos; O60337; Tbio. DR PRO; PR:O60337; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; O60337; protein. DR Bgee; ENSG00000145495; Expressed in Brodmann (1909) area 23 and 208 other tissues. DR ExpressionAtlas; O60337; baseline and differential. DR Genevisible; O60337; HS. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0044322; C:endoplasmic reticulum quality control compartment; IEA:GOC. DR GO; GO:0000835; C:ER ubiquitin ligase complex; IC:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; IDA:ParkinsonsUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IPI:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:1990381; F:ubiquitin-specific protease binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:1904380; P:endoplasmic reticulum mannose trimming; TAS:Reactome. DR GO; GO:0036503; P:ERAD pathway; TAS:ParkinsonsUK-UCL. DR GO; GO:0010498; P:proteasomal protein catabolic process; IDA:ParkinsonsUK-UCL. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; IBA:GO_Central. DR CDD; cd16702; RING_CH-C4HC3_MARCH6; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR011016; Znf_RING-CH. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR PANTHER; PTHR13145:SF0; E3 UBIQUITIN-PROTEIN LIGASE MARCHF6; 1. DR PANTHER; PTHR13145; SSM4 PROTEIN; 1. DR Pfam; PF12906; RINGv; 1. DR SMART; SM00744; RINGv; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR PROSITE; PS51292; ZF_RING_CH; 1. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; Endoplasmic reticulum; Epilepsy; KW Membrane; Metal-binding; Reference proteome; Transferase; Transmembrane; KW Transmembrane helix; Ubl conjugation; Ubl conjugation pathway; Zinc; KW Zinc-finger. FT CHAIN 1..910 FT /note="E3 ubiquitin-protein ligase MARCHF6" FT /id="PRO_0000274298" FT TOPO_DOM 1..91 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:15673284, FT ECO:0000305|PubMed:16373356" FT TRANSMEM 92..112 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 113..142 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 143..163 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 164..283 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 284..304 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 305..336 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 337..357 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 358..376 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 377..397 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 398..421 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 422..442 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 443..480 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 481..501 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 502..519 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 520..540 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 541..632 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 633..653 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 654..678 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 679..699 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 700..721 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 722..742 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 743..764 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 765..785 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 786..815 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 816..836 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 837..848 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 849..869 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 870..910 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:16373356" FT ZN_FING 1..62 FT /note="RING-CH-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT REGION 185..256 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 224..246 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 9 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT BINDING 12 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT BINDING 26 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT BINDING 28 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT BINDING 36 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT BINDING 39 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT BINDING 52 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT BINDING 55 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00623" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" FT VAR_SEQ 7..112 FT /note="DICRVCRSEGTPEKPLYHPCVCTGSIKFIHQECLVQWLKHSRKEYCELCKHR FT FAFTPIYSPDMPSRLPIQDIFAGLVTSIGTAIRYWFHYTLVAFAWLGVVPLTAC -> G FT (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_047035" FT VAR_SEQ 64..112 FT /note="IYSPDMPSRLPIQDIFAGLVTSIGTAIRYWFHYTLVAFAWLGVVPLTAC -> FT S (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_047036" FT VARIANT 622 FT /note="P -> L (in dbSNP:rs1062914)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_030251" FT MUTAGEN 9 FT /note="C->A: Abolishes auto-ubiquitination. Loss of FT ubiquitin ligase activity." FT /evidence="ECO:0000269|PubMed:15673284, FT ECO:0000269|PubMed:24449766" FT CONFLICT 380 FT /note="V -> VG (in Ref. 6; AAB66840)" FT /evidence="ECO:0000305" FT CONFLICT 384 FT /note="G -> GS (in Ref. 6; AAB66840)" FT /evidence="ECO:0000305" FT CONFLICT 390 FT /note="C -> WW (in Ref. 6; AAB66840)" FT /evidence="ECO:0000305" FT CONFLICT 395 FT /note="D -> G (in Ref. 6; AAB66840)" FT /evidence="ECO:0000305" FT CONFLICT 399 FT /note="L -> LG (in Ref. 6; AAB66840)" FT /evidence="ECO:0000305" FT CONFLICT 546 FT /note="R -> K (in Ref. 6; AAB66840)" FT /evidence="ECO:0000305" SQ SEQUENCE 910 AA; 102545 MW; C7A96FEA45B5CA8D CRC64; MDTAEEDICR VCRSEGTPEK PLYHPCVCTG SIKFIHQECL VQWLKHSRKE YCELCKHRFA FTPIYSPDMP SRLPIQDIFA GLVTSIGTAI RYWFHYTLVA FAWLGVVPLT ACRIYKCLFT GSVSSLLTLP LDMLSTENLL ADCLQGCFVV TCTLCAFISL VWLREQIVHG GAPIWLEHAA PPFNAAGHHQ NEAPAGGNGA ENVAADQPAN PPAENAVVGE NPDAQDDQAE EEEEDNEEED DAGVEDAADA NNGAQDDMNW NALEWDRAAE ELTWERMLGL DGSLVFLEHV FWVVSLNTLF ILVFAFCPYH IGHFSLVGLG FEEHVQASHF EGLITTIVGY ILLAITLIIC HGLATLVKFH RSRRLLGVCY IVVKVSLLVV VEIGVFPLIC GWWLDICSLE MFDATLKDRE LSFQSAPGTT MFLHWLVGMV YVFYFASFIL LLREVLRPGV LWFLRNLNDP DFNPVQEMIH LPIYRHLRRF ILSVIVFGSI VLLMLWLPIR IIKSVLPNFL PYNVMLYSDA PVSELSLELL LLQVVLPALL EQGHTRQWLK GLVRAWTVTA GYLLDLHSYL LGDQEENENS ANQQVNNNQH ARNNNAIPVV GEGLHAAHQA ILQQGGPVGF QPYRRPLNFP LRIFLLIVFM CITLLIASLI CLTLPVFAGR WLMSFWTGTA KIHELYTAAC GLYVCWLTIR AVTVMVAWMP QGRRVIFQKV KEWSLMIMKT LIVAVLLAGV VPLLLGLLFE LVIVAPLRVP LDQTPLFYPW QDWALGVLHA KIIAAITLMG PQWWLKTVIE QVYANGIRNI DLHYIVRKLA APVISVLLLS LCVPYVIASG VVPLLGVTAE MQNLVHRRIY PFLLMVVVLM AILSFQVRQF KRLYEHIKND KYLVGQRLVN YERKSGKQGS SPPPPQSSQE //