Full text data of HUWE1
HUWE1
(KIAA0312, KIAA1578, UREB1)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
E3 ubiquitin-protein ligase HUWE1; 6.3.2.- (ARF-binding protein 1; ARF-BP1; HECT, UBA and WWE domain-containing protein 1; Homologous to E6AP carboxyl terminus homologous protein 9; HectH9; Large structure of UREB1; LASU1; Mcl-1 ubiquitin ligase E3; Mule; Upstream regulatory element-binding protein 1; URE-B1; URE-binding protein 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
E3 ubiquitin-protein ligase HUWE1; 6.3.2.- (ARF-binding protein 1; ARF-BP1; HECT, UBA and WWE domain-containing protein 1; Homologous to E6AP carboxyl terminus homologous protein 9; HectH9; Large structure of UREB1; LASU1; Mcl-1 ubiquitin ligase E3; Mule; Upstream regulatory element-binding protein 1; URE-B1; URE-binding protein 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00456919
IPI00456919 PREDICTED: upstream regulatory element binding protein 1 probable E3 ubiquitin-protein ligase, which mediates ubiquitination and subsequent proteasomal degradation of target proteins. May inhibit p53/TP53 transactivation, possibly by mediating ubiquitination of it soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00456919 PREDICTED: upstream regulatory element binding protein 1 probable E3 ubiquitin-protein ligase, which mediates ubiquitination and subsequent proteasomal degradation of target proteins. May inhibit p53/TP53 transactivation, possibly by mediating ubiquitination of it soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
Q7Z6Z7
ID HUWE1_HUMAN Reviewed; 4374 AA.
AC Q7Z6Z7; O15029; Q4G2Z2; Q5H961; Q6P4D0; Q8NG67; Q9BUI0; Q9HCJ4;
read moreAC Q9NSL6; Q9P0A9;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2005, sequence version 3.
DT 22-JAN-2014, entry version 119.
DE RecName: Full=E3 ubiquitin-protein ligase HUWE1;
DE EC=6.3.2.-;
DE AltName: Full=ARF-binding protein 1;
DE Short=ARF-BP1;
DE AltName: Full=HECT, UBA and WWE domain-containing protein 1;
DE AltName: Full=Homologous to E6AP carboxyl terminus homologous protein 9;
DE Short=HectH9;
DE AltName: Full=Large structure of UREB1;
DE Short=LASU1;
DE AltName: Full=Mcl-1 ubiquitin ligase E3;
DE Short=Mule;
DE AltName: Full=Upstream regulatory element-binding protein 1;
DE Short=URE-B1;
DE Short=URE-binding protein 1;
GN Name=HUWE1; Synonyms=KIAA0312, KIAA1578, UREB1; ORFNames=HSPC272;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH
RP CDKN2A, AND MUTAGENESIS OF CYS-4341.
RX PubMed=15989956; DOI=10.1016/j.cell.2005.03.037;
RA Chen D., Kon N., Li M., Zhang W., Qin J., Gu W.;
RT "ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor.";
RL Cell 121:1071-1083(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND MUTAGENESIS OF
RP CYS-4341.
RX PubMed=15989957; DOI=10.1016/j.cell.2005.06.009;
RA Zhong Q., Gao W., Du F., Wang X.;
RT "Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the
RT polyubiquitination of Mcl-1 and regulates apoptosis.";
RL Cell 121:1085-1095(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RX PubMed=15767685; DOI=10.1128/MCB.25.7.2819-2831.2005;
RA Liu Z., Oughtred R., Wing S.S.;
RT "Characterization of E3Histone, a novel testis ubiquitin protein
RT ligase which ubiquitinates histones.";
RL Mol. Cell. Biol. 25:2819-2831(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 959-4374 (ISOFORM 3).
RC TISSUE=Brain;
RA Miyazaki K., Okamoto Y., Sakamoto M., Kato C., Ozaki T., Watanabe K.,
RA Nakagawara A.;
RT "Homo sapiens LASU1 (large structure of UREB1) mRNA, complete cds.";
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1166-4374 (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VII.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 4:141-150(1997).
RN [7]
RP SEQUENCE REVISION TO 2310.
RA Ohara O., Nagase T., Kikuno R., Nomura N.;
RL Submitted (SEP-2011) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1246-2418.
RC TISSUE=Brain;
RX PubMed=10997877; DOI=10.1093/dnares/7.4.271;
RA Nagase T., Kikuno R., Nakayama M., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes.
RT XVIII. The complete sequences of 100 new cDNA clones from brain which
RT code for large proteins in vitro.";
RL DNA Res. 7:273-281(2000).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2451-4374.
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for
RT 300 previously undefined genes expressed in CD34+ hematopoietic
RT stem/progenitor cells.";
RL Genome Res. 10:1546-1560(2000).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3953-4374.
RC TISSUE=Ovary, and Placenta;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4029-4374.
RA Kim J.W., Lee Y., Hong Y.M., Hong M., Choe I.S.;
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4067-4374.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4320-4374.
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [14]
RP FUNCTION, TISSUE SPECIFICITY, AND MUTAGENESIS OF TYR-4268 AND
RP CYS-4341.
RX PubMed=15567145; DOI=10.1016/j.bbrc.2004.11.004;
RA Yoon S.Y., Lee Y., Kim J.H., Chung A.-S., Joo J.H., Kim C.-N.,
RA Kim N.-S., Choe I.S., Kim J.W.;
RT "Over-expression of human UREB1 in colorectal cancer: HECT domain of
RT human UREB1 inhibits the activity of tumor suppressor p53 protein.";
RL Biochem. Biophys. Res. Commun. 326:7-17(2005).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2362, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1395; SER-1907;
RP SER-2362; SER-2887 AND SER-2918, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [17]
RP FUNCTION, AND INTERACTION WITH CDC6.
RX PubMed=17567951; DOI=10.1091/mbc.E07-02-0173;
RA Hall J.R., Kow E., Nevis K.R., Lu C.K., Luce K.S., Zhong Q.,
RA Cook J.G.;
RT "Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA
RT damage.";
RL Mol. Biol. Cell 18:3340-3350(2007).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2362, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [22]
RP FUNCTION, INTERACTION WITH MYCN, AND MUTAGENESIS OF CYS-4341.
RX PubMed=18488021; DOI=10.1038/ncb1727;
RA Zhao X., Heng J.I.-T., Guardavaccaro D., Jiang R., Pagano M.,
RA Guillemot F., Iavarone A., Lasorella A.;
RT "The HECT-domain ubiquitin ligase Huwe1 controls neural
RT differentiation and proliferation by destabilizing the N-Myc
RT oncoprotein.";
RL Nat. Cell Biol. 10:643-653(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1368; SER-1907;
RP SER-2362; SER-2365; SER-2887; SER-3662; SER-3919; THR-3924 AND
RP THR-3927, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH POLB.
RX PubMed=19713937; DOI=10.1038/emboj.2009.243;
RA Parsons J.L., Tait P.S., Finch D., Dianova I.I., Edelmann M.J.,
RA Khoronenkova S.V., Kessler B.M., Sharma R.A., McKenna W.G.,
RA Dianov G.L.;
RT "Ubiquitin ligase ARF-BP1/Mule modulates base excision repair.";
RL EMBO J. 28:3207-3215(2009).
RN [26]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1370; SER-1395;
RP SER-1907; SER-2362; SER-2391; SER-2595; SER-2619; THR-2751; SER-2887;
RP SER-3116; SER-3752; SER-3757; SER-3808; SER-3816; SER-3919 AND
RP THR-3924, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084; SER-1368;
RP SER-1395; THR-1722; SER-1907; SER-2362; SER-2365; SER-2595; SER-3127;
RP SER-3662; SER-3757; SER-3760 AND SER-3919, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084; SER-1907; SER-2362
RP AND SER-2365, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [31]
RP STRUCTURE BY NMR OF 1317-1356.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of RSGI RUH-074, a human UBA domain.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 4005-4374.
RG Structural genomics consortium (SGC);
RT "Hect domain of human huwe1/mule.";
RL Submitted (MAY-2009) to the PDB data bank.
RN [33]
RP VARIANTS MRXS-TURNER HIS-2981; TRP-4013 AND CYS-4187, AND INVOLVEMENT
RP IN MRX17.
RX PubMed=18252223; DOI=10.1016/j.ajhg.2007.11.002;
RA Froyen G., Corbett M., Vandewalle J., Jarvela I., Lawrence O.,
RA Meldrum C., Bauters M., Govaerts K., Vandeleur L., Van Esch H.,
RA Chelly J., Sanlaville D., van Bokhoven H., Ropers H.-H.,
RA Laumonnier F., Ranieri E., Schwartz C.E., Abidi F., Tarpey P.S.,
RA Futreal P.A., Whibley A., Raymond F.L., Stratton M.R., Fryns J.-P.,
RA Scott R., Peippo M., Sipponen M., Partington M., Mowat D., Field M.,
RA Hackett A., Marynen P., Turner G., Gecz J.;
RT "Submicroscopic duplications of the hydroxysteroid dehydrogenase
RT HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental
RT retardation.";
RL Am. J. Hum. Genet. 82:432-443(2008).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which mediates
CC ubiquitination and subsequent proteasomal degradation of target
CC proteins. Regulates apoptosis by catalyzing the polyubiquitination
CC and degradation of MCL1. Mediates monoubiquitination of DNA
CC polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby
CC playing a role in base-excision repair. Also ubiquitinates the
CC p53/TP53 tumor suppressor and core histones including H1, H2A,
CC H2B, H3 and H4. Binds to an upstream initiator-like sequence in
CC the preprodynorphin gene. Regulates neural differentiation and
CC proliferation by catalyzing the polyubiquitination and degradation
CC of MYCN. May regulate abundance of CDC6 after DNA damage by
CC polyubiquitinating and targeting CDC6 to degradation.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with isoform p14ARF of CDKN2A which strongly
CC inhibits HUWE1 ubiquitin ligase activity. Interacts with MYCN,
CC POLB and CDC6.
CC -!- INTERACTION:
CC Q8N726:CDKN2A; NbExp=4; IntAct=EBI-625934, EBI-625922;
CC P04637:TP53; NbExp=3; IntAct=EBI-625934, EBI-366083;
CC Q13107:USP4; NbExp=4; IntAct=EBI-625934, EBI-723290;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Mainly expressed in
CC the cytoplasm of most tissues, except in the nucleus of
CC spermatogonia, primary spermatocytes and neuronal cells (By
CC similarity). Predominantly cytosolic or perinuclear in some
CC colorectal carcinoma cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=LASU1, Large structure of UREB1;
CC IsoId=Q7Z6Z7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q7Z6Z7-2; Sequence=VSP_011146;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q7Z6Z7-3; Sequence=VSP_015272;
CC -!- TISSUE SPECIFICITY: Weakly expressed in heart, brain and placenta
CC but not in other tissues. Expressed in a number of cell lines,
CC predominantly in those from colorectal carcinomas.
CC -!- DOMAIN: The HECT domain mediates inhibition of the transcriptional
CC activity of p53.
CC -!- PTM: Phosphorylated on tyrosine; phosphorylation is probably
CC required for its ability to inhibit TP53 transactivation (By
CC similarity).
CC -!- DISEASE: Mental retardation, X-linked, syndromic, Turner type
CC (MRXST) [MIM:300706]: A syndrome characterized by the association
CC of mental retardation with macrocephaly and variable contractures.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Mental retardation, X-linked 17 (MRX17) [MIM:300705]: A
CC disorder characterized by significantly below average general
CC intellectual functioning associated with impairments in adaptive
CC behavior and manifested during the developmental period.
CC Intellectual deficiency is the only primary symptom of non-
CC syndromic X-linked mental retardation, while syndromic mental
CC retardation presents with associated physical, neurological and/or
CC psychiatric manifestations. Note=The gene represented in this
CC entry is involved in disease pathogenesis. A chromosomal
CC microduplication involving HSD17B10 and HUWE1 has been found in
CC patients with mental retardation.
CC -!- SIMILARITY: Belongs to the UPL family. TOM1/PTR1 subfamily.
CC -!- SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein
CC ligase) domain.
CC -!- SIMILARITY: Contains 1 UBA domain.
CC -!- SIMILARITY: Contains 1 UIM (ubiquitin-interacting motif) repeat.
CC -!- SIMILARITY: Contains 1 WWE domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC62492.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAF28950.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=AAF28950.1; Type=Frameshift; Positions=4356;
CC Sequence=BAB13404.1; Type=Miscellaneous discrepancy; Note=Chimeric cDNA, contains the C-terminal part of ATP5I;
CC Sequence=BAC06833.1; Type=Frameshift; Positions=982, 1055;
CC -----------------------------------------------------------------------
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DR EMBL; AY772009; AAV90838.1; -; mRNA.
DR EMBL; DQ097177; AAY98258.1; -; mRNA.
DR EMBL; AY929612; AAX24125.1; -; mRNA.
DR EMBL; AL592046; CAI39580.1; -; Genomic_DNA.
DR EMBL; Z94044; CAI39580.1; JOINED; Genomic_DNA.
DR EMBL; Z97054; CAI39580.1; JOINED; Genomic_DNA.
DR EMBL; Z94044; CAI42354.1; -; Genomic_DNA.
DR EMBL; AL592046; CAI42354.1; JOINED; Genomic_DNA.
DR EMBL; Z97054; CAI42354.1; JOINED; Genomic_DNA.
DR EMBL; Z97054; CAI42654.1; -; Genomic_DNA.
DR EMBL; AL592046; CAI42654.1; JOINED; Genomic_DNA.
DR EMBL; Z94044; CAI42654.1; JOINED; Genomic_DNA.
DR EMBL; AB071605; BAC06833.1; ALT_FRAME; mRNA.
DR EMBL; AB002310; BAA20771.3; -; mRNA.
DR EMBL; AB046798; BAB13404.1; ALT_SEQ; mRNA.
DR EMBL; AF161390; AAF28950.1; ALT_SEQ; mRNA.
DR EMBL; BC002602; AAH02602.2; -; mRNA.
DR EMBL; BC063505; AAH63505.1; -; mRNA.
DR EMBL; AF057569; AAC62492.1; ALT_INIT; mRNA.
DR EMBL; CR456813; CAG33094.1; -; mRNA.
DR EMBL; AL162050; CAB82393.1; -; mRNA.
DR PIR; T47165; T47165.
DR RefSeq; NP_113584.3; NM_031407.6.
DR RefSeq; XP_005262022.1; XM_005261965.1.
DR RefSeq; XP_005262023.1; XM_005261966.1.
DR RefSeq; XP_005262024.1; XM_005261967.1.
DR RefSeq; XP_005262027.1; XM_005261970.1.
DR RefSeq; XP_005278018.1; XM_005277961.1.
DR RefSeq; XP_005278019.1; XM_005277962.1.
DR RefSeq; XP_005278020.1; XM_005277963.1.
DR RefSeq; XP_005278023.1; XM_005277966.1.
DR UniGene; Hs.136905; -.
DR PDB; 2EKK; NMR; -; A=1317-1356.
DR PDB; 3G1N; X-ray; 2.60 A; A/B=4005-4374.
DR PDB; 3H1D; X-ray; 1.89 A; A=3993-4374.
DR PDBsum; 2EKK; -.
DR PDBsum; 3G1N; -.
DR PDBsum; 3H1D; -.
DR ProteinModelPortal; Q7Z6Z7; -.
DR SMR; Q7Z6Z7; 1310-1356, 4000-4366.
DR DIP; DIP-34362N; -.
DR IntAct; Q7Z6Z7; 24.
DR MINT; MINT-1576525; -.
DR PhosphoSite; Q7Z6Z7; -.
DR DMDM; 73915353; -.
DR PaxDb; Q7Z6Z7; -.
DR PRIDE; Q7Z6Z7; -.
DR Ensembl; ENST00000262854; ENSP00000262854; ENSG00000086758.
DR Ensembl; ENST00000342160; ENSP00000340648; ENSG00000086758.
DR GeneID; 10075; -.
DR KEGG; hsa:10075; -.
DR UCSC; uc004dsp.4; human.
DR CTD; 10075; -.
DR GeneCards; GC0XM053575; -.
DR HGNC; HGNC:30892; HUWE1.
DR HPA; CAB022718; -.
DR HPA; HPA002548; -.
DR MIM; 300697; gene.
DR MIM; 300705; phenotype.
DR MIM; 300706; phenotype.
DR neXtProt; NX_Q7Z6Z7; -.
DR Orphanet; 85328; Intellectual deficit, X-linked, Turner type.
DR PharmGKB; PA128394567; -.
DR eggNOG; COG5021; -.
DR HOVERGEN; HBG080254; -.
DR KO; K10592; -.
DR OMA; GMTQEVG; -.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR ChiTaRS; HUWE1; human.
DR EvolutionaryTrace; Q7Z6Z7; -.
DR GeneWiki; HUWE1; -.
DR GenomeRNAi; 10075; -.
DR NextBio; 38085; -.
DR PRO; PR:Q7Z6Z7; -.
DR ArrayExpress; Q7Z6Z7; -.
DR Bgee; Q7Z6Z7; -.
DR Genevestigator; Q7Z6Z7; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0006284; P:base-excision repair; IMP:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0016574; P:histone ubiquitination; IDA:UniProtKB.
DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB.
DR GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IBA:RefGenome.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR025527; DUF4414.
DR InterPro; IPR010309; E3_Ub_ligase_DUF908.
DR InterPro; IPR010314; E3_Ub_ligase_DUF913.
DR InterPro; IPR000569; HECT.
DR InterPro; IPR009060; UBA-like.
DR InterPro; IPR015940; UBA/transl_elong_EF1B_N_euk.
DR InterPro; IPR000449; UBA/Ts_N.
DR InterPro; IPR004170; WWE-dom.
DR Pfam; PF14377; DUF4414; 1.
DR Pfam; PF06012; DUF908; 1.
DR Pfam; PF06025; DUF913; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00627; UBA; 1.
DR Pfam; PF02825; WWE; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00165; UBA; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS50030; UBA; 1.
DR PROSITE; PS50330; UIM; FALSE_NEG.
DR PROSITE; PS50918; WWE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Chromosomal rearrangement;
KW Complete proteome; Cytoplasm; Differentiation; Disease mutation;
KW DNA damage; DNA repair; DNA-binding; Ligase; Mental retardation;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Ubl conjugation pathway.
FT CHAIN 1 4374 E3 ubiquitin-protein ligase HUWE1.
FT /FTId=PRO_0000120340.
FT DOMAIN 1316 1355 UBA.
FT REPEAT 1370 1389 UIM.
FT DOMAIN 1603 1680 WWE.
FT DOMAIN 4038 4374 HECT.
FT COMPBIAS 2295 2469 Glu-rich.
FT COMPBIAS 2427 2490 Asp-rich.
FT COMPBIAS 3483 3550 Thr-rich.
FT ACT_SITE 4341 4341 Glycyl thioester intermediate.
FT MOD_RES 1084 1084 Phosphoserine.
FT MOD_RES 1368 1368 Phosphoserine.
FT MOD_RES 1370 1370 Phosphoserine.
FT MOD_RES 1395 1395 Phosphoserine.
FT MOD_RES 1722 1722 Phosphothreonine.
FT MOD_RES 1907 1907 Phosphoserine.
FT MOD_RES 2362 2362 Phosphoserine.
FT MOD_RES 2365 2365 Phosphoserine.
FT MOD_RES 2391 2391 Phosphoserine.
FT MOD_RES 2595 2595 Phosphoserine.
FT MOD_RES 2619 2619 Phosphoserine.
FT MOD_RES 2751 2751 Phosphothreonine.
FT MOD_RES 2887 2887 Phosphoserine.
FT MOD_RES 2918 2918 Phosphoserine.
FT MOD_RES 3116 3116 Phosphoserine.
FT MOD_RES 3127 3127 Phosphoserine.
FT MOD_RES 3662 3662 Phosphoserine.
FT MOD_RES 3752 3752 Phosphoserine.
FT MOD_RES 3757 3757 Phosphoserine.
FT MOD_RES 3760 3760 Phosphoserine.
FT MOD_RES 3808 3808 Phosphoserine.
FT MOD_RES 3816 3816 Phosphoserine.
FT MOD_RES 3919 3919 Phosphoserine.
FT MOD_RES 3924 3924 Phosphothreonine.
FT MOD_RES 3927 3927 Phosphothreonine.
FT VAR_SEQ 982 990 Missing (in isoform 3).
FT /FTId=VSP_015272.
FT VAR_SEQ 3016 3031 Missing (in isoform 2).
FT /FTId=VSP_011146.
FT VARIANT 483 483 N -> S (in dbSNP:rs41307640).
FT /FTId=VAR_061986.
FT VARIANT 2981 2981 R -> H (in MRXS-Turner).
FT /FTId=VAR_045670.
FT VARIANT 4013 4013 R -> W (in MRXS-Turner).
FT /FTId=VAR_045671.
FT VARIANT 4187 4187 R -> C (in MRXS-Turner).
FT /FTId=VAR_045672.
FT MUTAGEN 4268 4268 Y->S: Loss of activity.
FT MUTAGEN 4341 4341 C->A,D: Loss of activity.
FT CONFLICT 1111 1111 K -> N (in Ref. 5; BAC06833).
FT CONFLICT 1124 1124 P -> L (in Ref. 1; AAV90838 and 5;
FT BAC06833).
FT CONFLICT 1190 1190 D -> H (in Ref. 5; BAC06833).
FT CONFLICT 1962 1962 Missing (in Ref. 6; BAA20771).
FT CONFLICT 2525 2525 H -> Y (in Ref. 5; BAC06833 and 9;
FT AAF28950).
FT CONFLICT 4022 4022 R -> L (in Ref. 10; AAH02602).
FT HELIX 1319 1329
FT HELIX 1332 1341
FT HELIX 1345 1353
FT HELIX 3994 4008
FT TURN 4009 4011
FT STRAND 4016 4021
FT HELIX 4023 4025
FT HELIX 4026 4034
FT HELIX 4041 4043
FT STRAND 4044 4050
FT HELIX 4061 4072
FT HELIX 4076 4078
FT STRAND 4080 4083
FT TURN 4085 4087
FT STRAND 4088 4093
FT HELIX 4095 4099
FT HELIX 4103 4120
FT HELIX 4130 4137
FT HELIX 4143 4145
FT HELIX 4146 4149
FT HELIX 4151 4162
FT HELIX 4165 4167
FT STRAND 4168 4170
FT STRAND 4172 4175
FT TURN 4176 4178
FT STRAND 4181 4183
FT HELIX 4186 4189
FT STRAND 4193 4197
FT TURN 4200 4202
FT HELIX 4203 4215
FT HELIX 4217 4219
FT HELIX 4220 4233
FT HELIX 4236 4239
FT HELIX 4244 4252
FT HELIX 4259 4264
FT STRAND 4266 4271
FT HELIX 4276 4287
FT HELIX 4290 4301
FT STRAND 4302 4304
FT HELIX 4311 4313
FT STRAND 4317 4320
FT STRAND 4323 4328
FT STRAND 4337 4339
FT HELIX 4340 4342
FT STRAND 4344 4348
FT HELIX 4353 4365
SQ SEQUENCE 4374 AA; 481891 MW; FA9D3A7712F6393B CRC64;
MKVDRTKLKK TPTEAPADCR ALIDKLKVCN DEQLLLELQQ IKTWNIGKCE LYHWVDLLDR
FDGILADAGQ TVENMSWMLV CDRPEREQLK MLLLAVLNFT ALLIEYSFSR HLYSSIEHLT
TLLASSDMQV VLAVLNLLYV FSKRSNYITR LGSDKRTPLL TRLQHLAESW GGKENGFGLA
ECCRDLHMMK YPPSATTLHF EFYADPGAEV KIEKRTTSNT LHYIHIEQLD KISESPSEIM
ESLTKMYSIP KDKQMLLFTH IRLAHGFSNH RKRLQAVQAR LHAISILVYS NALQESANSI
LYNGLIEELV DVLQITDKQL MEIKAASLRT LTSIVHLERT PKLSSIIDCT GTASYHGFLP
VLVRNCIQAM IDPSMDPYPH QFATALFSFL YHLASYDAGG EALVSCGMME ALLKVIKFLG
DEQDQITFVT RAVRVVDLIT NLDMAAFQSH SGLSIFIYRL EHEVDLCRKE CPFVIKPKIQ
RPNTTQEGEE METDMDGVQC IPQRAALLKS MLNFLKKAIQ DPAFSDGIRH VMDGSLPTSL
KHIISNAEYY GPSLFLLATE VVTVFVFQEP SLLSSLQDNG LTDVMLHALL IKDVPATREV
LGSLPNVFSA LCLNARGLQS FVQCQPFERL FKVLLSPDYL PAMRRRRSSD PLGDTASNLG
SAVDELMRHQ PTLKTDATTA IIKLLEEICN LGRDPKYICQ KPSIQKADGT ATAPPPRSNH
AAEEASSEDE EEEEVQAMQS FNSTQQNETE PNQQVVGTEE RIPIPLMDYI LNVMKFVESI
LSNNTTDDHC QEFVNQKGLL PLVTILGLPN LPIDFPTSAA CQAVAGVCKS ILTLSHEPKV
LQEGLLQLDS ILSSLEPLHR PIESPGGSVL LRELACAGNV ADATLSAQAT PLLHALTAAH
AYIMMFVHTC RVGQSEIRSI SVNQWGSQLG LSVLSKLSQL YCSLVWESTV LLSLCTPNSL
PSGCEFGQAD MQKLVPKDEK AGTTQGGKRS DGEQDGAAGS MDASTQGLLE GIGLDGDTLA
PMETDEPTAS DSKGKSKITP AMAARIKQIK PLLSASSRLG RALAELFGLL VKLCVGSPVR
QRRSHHAAST TTAPTPAARS TASALTKLLT KGLSWQPPPY TPTPRFRLTF FICSVGFTSP
MLFDERKYPY HLMLQKFLCS GGHNALFETF NWALSMGGKV PVSEGLEHSD LPDGTGEFLD
AWLMLVEKMV NPTTVLESPH SLPAKLPGGV QNFPQFSALR FLVVTQKAAF TCIKNLWNRK
PLKVYGGRMA ESMLAILCHI LRGEPVIRER LSKEKEGSRG EEDTGQEEGG SRREPQVNQQ
QLQQLMDMGF TREHAMEALL NTSTMEQATE YLLTHPPPIM GGVVRDLSMS EEDQMMRAIA
MSLGQDIPMD QRAESPEEVA CRKEEEERKA REKQEEEEAK CLEKFQDADP LEQDELHTFT
DTMLPGCFHL LDELPDTVYR VCDLIMTAIK RNGADYRDMI LKQVVNQVWE AADVLIKAAL
PLTTSDTKTV SEWISQMATL PQASNLATRI LLLTLLFEEL KLPCAWVVES SGILNVLIKL
LEVVQPCLQA AKEQKEVQTP KWITPVLLLI DFYEKTAISS KRRAQMTKYL QSNSNNWRWF
DDRSGRWCSY SASNNSTIDS AWKSGETSVR FTAGRRRYTV QFTTMVQVNE ETGNRRPVML
TLLRVPRLNK NSKNSNGQEL EKTLEESKEM DIKRKENKGN DTPLALESTN TEKETSLEET
KIGEILIQGL TEDMVTVLIR ACVSMLGVPV DPDTLHATLR LCLRLTRDHK YAMMFAELKS
TRMILNLTQS SGFNGFTPLV TLLLRHIIED PCTLRHTMEK VVRSAATSGA GSTTSGVVSG
SLGSREINYI LRVLGPAACR NPDIFTEVAN CCIRIALPAP RGSGTASDDE FENLRIKGPN
AVQLVKTTPL KPSPLPVIPD TIKEVIYDML NALAAYHAPE EADKSDPKPG VMTQEVGQLL
QDMGDDVYQQ YRSLTRQSSD FDTQSGFSIN SQVFAADGAS TETSASGTSQ GEASTPEESR
DGKKDKEGDR ASEEGKQKGK GSKPLMPTST ILRLLAELVR SYVGIATLIA NYSYTVGQSE
LIKEDCSVLA FVLDHLLPHT QNAEDKDTPA LARLFLASLA AAGSGTDAQV ALVNEVKAAL
GRALAMAEST EKHARLQAVM CIISTIMESC PSTSSFYSSA TAKTQHNGMN NIIRLFLKKG
LVNDLARVPH SLDLSSPNMA NTVNAALKPL ETLSRIVNQP SSLFGSKSAS SKNKSEQDAQ
GASQDSSSNQ QDPGEPGEAE VQEEDHDVTQ TEVADGDIMD GEAETDSVVI AGQPEVLSSQ
EMQVENELED LIDELLERDG GSGNSTIIVS RSGEDESQED VLMDEAPSNL SQASTLQANR
EDSMNILDPE DEEEHTQEED SSGSNEDEDD SQDEEEEEEE DEEDDQEDDE GEEGDEDDDD
DGSEMELDED YPDMNASPLV RFERFDREDD LIIEFDNMFS SATDIPPSPG NIPTTHPLMV
RHADHSSLTL GSGSSTTRLT QGIGRSQRTL RQLTANTGHT IHVHYPGNRQ PNPPLILQRL
LGPSAAADIL QLSSSLPLQS RGRARLLVGN DDVHIIARSD DELLDDFFHD QSTATSQAGT
LSSIPTALTR WTEECKVLDA ESMHDCVSVV KVSIVNHLEF LRDEELEERR EKRRKQLAEE
ETKITDKGKE DKENRDQSAQ CTASKSNDST EQNLSDGTPM PDSYPTTPSS TDAATSESKE
TLGTLQSSQQ QPTLPTPPAL GEVPQELQSP AGEGGSSTQL LMPVEPEELG PTRPSGEAET
TQMELSPAPT ITSLSPERAE DSDALTAVSS QLEGSPMDTS SLASCTLEEA VGDTSAAGSS
EQPRAGSSTP GDAPPAVAEV QGRSDGSGES AQPPEDSSPP ASSESSSTRD SAVAISGADS
RGILEEPLPS TSSEEEDPLA GISLPEGVDP SFLAALPDDI RREVLQNQLG IRPPTRTAPS
TNSSAPAVVG NPGVTEVSPE FLAALPPAIQ EEVLAQQRAE QQRRELAQNA SSDTPMDPVT
FIQTLPSDLR RSVLEDMEDS VLAVMPPDIA AEAQALRREQ EARQRQLMHE RLFGHSSTSA
LSAILRSPAF TSRLSGNRGV QYTRLAVQRG GTFQMGGSSS HNRPSGSNVD TLLRLRGRLL
LDHEALSCLL VLLFVDEPKL NTSRLHRVLR NLCYHAQTRH WVIRSLLSIL QRSSESELCI
ETPKLTTSEE KGKKSSKSCG SSSHENRPLD LLHKMESKSS NQLSWLSVSM DAALGCRTNI
FQIQRSGGRK HTEKHASGGS TVHIHPQAAP VVCRHVLDTL IQLAKVFPSH FTQQRTKETN
CESDRERGNK ACSPCSSQSS SSGICTDFWD LLVKLDNMNV SRKGKNSVKS VPVSAGGEGE
TSPYSLEASP LGQLMNMLSH PVIRRSSLLT EKLLRLLSLI SIALPENKVS EAQANSGSGA
SSTTTATSTT STTTTTAAST TPTPPTAPTP VTSAPALVAA TAISTIVVAA STTVTTPTTA
TTTVSISPTT KGSKSPAKVS DGGSSSTDFK MVSSGLTENQ LQLSVEVLTS HSCSEEGLED
AANVLLQLSR GDSGTRDTVL KLLLNGARHL GYTLCKQIGT LLAELREYNL EQQRRAQCET
LSPDGLPEEQ PQTTKLKGKM QSRFDMAENV VIVASQKRPL GGRELQLPSM SMLTSKTSTQ
KFFLRVLQVI IQLRDDTRRA NKKAKQTGRL GSSGLGSASS IQAAVRQLEA EADAIIQMVR
EGQRARRQQQ AATSESSQSE ASVRREESPM DVDQPSPSAQ DTQSIASDGT PQGEKEKEER
PPELPLLSEQ LSLDELWDML GECLKELEES HDQHAVLVLQ PAVEAFFLVH ATERESKPPV
RDTRESQLAH IKDEPPPLSP APLTPATPSS LDPFFSREPS SMHISSSLPP DTQKFLRFAE
THRTVLNQIL RQSTTHLADG PFAVLVDYIR VLDFDVKRKY FRQELERLDE GLRKEDMAVH
VRRDHVFEDS YRELHRKSPE EMKNRLYIVF EGEEGQDAGG LLREWYMIIS REMFNPMYAL
FRTSPGDRVT YTINPSSHCN PNHLSYFKFV GRIVAKAVYD NRLLECYFTR SFYKHILGKS
VRYTDMESED YHFYQGLVYL LENDVSTLGY DLTFSTEVQE FGVCEVRDLK PNGANILVTE
ENKKEYVHLV CQMRMTGAIR KQLAAFLEGF YEIIPKRLIS IFTEQELELL ISGLPTIDID
DLKSNTEYHK YQSNSIQIQW FWRALRSFDQ ADRAKFLQFV TGTSKVPLQG FAALEGMNGI
QKFQIHRDDR STDRLPSAHT CFNQLDLPAY ESFEKLRHML LLAIQECSEG FGLA
//
ID HUWE1_HUMAN Reviewed; 4374 AA.
AC Q7Z6Z7; O15029; Q4G2Z2; Q5H961; Q6P4D0; Q8NG67; Q9BUI0; Q9HCJ4;
read moreAC Q9NSL6; Q9P0A9;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2005, sequence version 3.
DT 22-JAN-2014, entry version 119.
DE RecName: Full=E3 ubiquitin-protein ligase HUWE1;
DE EC=6.3.2.-;
DE AltName: Full=ARF-binding protein 1;
DE Short=ARF-BP1;
DE AltName: Full=HECT, UBA and WWE domain-containing protein 1;
DE AltName: Full=Homologous to E6AP carboxyl terminus homologous protein 9;
DE Short=HectH9;
DE AltName: Full=Large structure of UREB1;
DE Short=LASU1;
DE AltName: Full=Mcl-1 ubiquitin ligase E3;
DE Short=Mule;
DE AltName: Full=Upstream regulatory element-binding protein 1;
DE Short=URE-B1;
DE Short=URE-binding protein 1;
GN Name=HUWE1; Synonyms=KIAA0312, KIAA1578, UREB1; ORFNames=HSPC272;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH
RP CDKN2A, AND MUTAGENESIS OF CYS-4341.
RX PubMed=15989956; DOI=10.1016/j.cell.2005.03.037;
RA Chen D., Kon N., Li M., Zhang W., Qin J., Gu W.;
RT "ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor.";
RL Cell 121:1071-1083(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND MUTAGENESIS OF
RP CYS-4341.
RX PubMed=15989957; DOI=10.1016/j.cell.2005.06.009;
RA Zhong Q., Gao W., Du F., Wang X.;
RT "Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the
RT polyubiquitination of Mcl-1 and regulates apoptosis.";
RL Cell 121:1085-1095(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RX PubMed=15767685; DOI=10.1128/MCB.25.7.2819-2831.2005;
RA Liu Z., Oughtred R., Wing S.S.;
RT "Characterization of E3Histone, a novel testis ubiquitin protein
RT ligase which ubiquitinates histones.";
RL Mol. Cell. Biol. 25:2819-2831(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 959-4374 (ISOFORM 3).
RC TISSUE=Brain;
RA Miyazaki K., Okamoto Y., Sakamoto M., Kato C., Ozaki T., Watanabe K.,
RA Nakagawara A.;
RT "Homo sapiens LASU1 (large structure of UREB1) mRNA, complete cds.";
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1166-4374 (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VII.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 4:141-150(1997).
RN [7]
RP SEQUENCE REVISION TO 2310.
RA Ohara O., Nagase T., Kikuno R., Nomura N.;
RL Submitted (SEP-2011) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1246-2418.
RC TISSUE=Brain;
RX PubMed=10997877; DOI=10.1093/dnares/7.4.271;
RA Nagase T., Kikuno R., Nakayama M., Hirosawa M., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes.
RT XVIII. The complete sequences of 100 new cDNA clones from brain which
RT code for large proteins in vitro.";
RL DNA Res. 7:273-281(2000).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2451-4374.
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for
RT 300 previously undefined genes expressed in CD34+ hematopoietic
RT stem/progenitor cells.";
RL Genome Res. 10:1546-1560(2000).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3953-4374.
RC TISSUE=Ovary, and Placenta;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4029-4374.
RA Kim J.W., Lee Y., Hong Y.M., Hong M., Choe I.S.;
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4067-4374.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4320-4374.
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [14]
RP FUNCTION, TISSUE SPECIFICITY, AND MUTAGENESIS OF TYR-4268 AND
RP CYS-4341.
RX PubMed=15567145; DOI=10.1016/j.bbrc.2004.11.004;
RA Yoon S.Y., Lee Y., Kim J.H., Chung A.-S., Joo J.H., Kim C.-N.,
RA Kim N.-S., Choe I.S., Kim J.W.;
RT "Over-expression of human UREB1 in colorectal cancer: HECT domain of
RT human UREB1 inhibits the activity of tumor suppressor p53 protein.";
RL Biochem. Biophys. Res. Commun. 326:7-17(2005).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2362, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1395; SER-1907;
RP SER-2362; SER-2887 AND SER-2918, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [17]
RP FUNCTION, AND INTERACTION WITH CDC6.
RX PubMed=17567951; DOI=10.1091/mbc.E07-02-0173;
RA Hall J.R., Kow E., Nevis K.R., Lu C.K., Luce K.S., Zhong Q.,
RA Cook J.G.;
RT "Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA
RT damage.";
RL Mol. Biol. Cell 18:3340-3350(2007).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2362, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [22]
RP FUNCTION, INTERACTION WITH MYCN, AND MUTAGENESIS OF CYS-4341.
RX PubMed=18488021; DOI=10.1038/ncb1727;
RA Zhao X., Heng J.I.-T., Guardavaccaro D., Jiang R., Pagano M.,
RA Guillemot F., Iavarone A., Lasorella A.;
RT "The HECT-domain ubiquitin ligase Huwe1 controls neural
RT differentiation and proliferation by destabilizing the N-Myc
RT oncoprotein.";
RL Nat. Cell Biol. 10:643-653(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1368; SER-1907;
RP SER-2362; SER-2365; SER-2887; SER-3662; SER-3919; THR-3924 AND
RP THR-3927, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH POLB.
RX PubMed=19713937; DOI=10.1038/emboj.2009.243;
RA Parsons J.L., Tait P.S., Finch D., Dianova I.I., Edelmann M.J.,
RA Khoronenkova S.V., Kessler B.M., Sharma R.A., McKenna W.G.,
RA Dianov G.L.;
RT "Ubiquitin ligase ARF-BP1/Mule modulates base excision repair.";
RL EMBO J. 28:3207-3215(2009).
RN [26]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1370; SER-1395;
RP SER-1907; SER-2362; SER-2391; SER-2595; SER-2619; THR-2751; SER-2887;
RP SER-3116; SER-3752; SER-3757; SER-3808; SER-3816; SER-3919 AND
RP THR-3924, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084; SER-1368;
RP SER-1395; THR-1722; SER-1907; SER-2362; SER-2365; SER-2595; SER-3127;
RP SER-3662; SER-3757; SER-3760 AND SER-3919, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1084; SER-1907; SER-2362
RP AND SER-2365, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [31]
RP STRUCTURE BY NMR OF 1317-1356.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of RSGI RUH-074, a human UBA domain.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 4005-4374.
RG Structural genomics consortium (SGC);
RT "Hect domain of human huwe1/mule.";
RL Submitted (MAY-2009) to the PDB data bank.
RN [33]
RP VARIANTS MRXS-TURNER HIS-2981; TRP-4013 AND CYS-4187, AND INVOLVEMENT
RP IN MRX17.
RX PubMed=18252223; DOI=10.1016/j.ajhg.2007.11.002;
RA Froyen G., Corbett M., Vandewalle J., Jarvela I., Lawrence O.,
RA Meldrum C., Bauters M., Govaerts K., Vandeleur L., Van Esch H.,
RA Chelly J., Sanlaville D., van Bokhoven H., Ropers H.-H.,
RA Laumonnier F., Ranieri E., Schwartz C.E., Abidi F., Tarpey P.S.,
RA Futreal P.A., Whibley A., Raymond F.L., Stratton M.R., Fryns J.-P.,
RA Scott R., Peippo M., Sipponen M., Partington M., Mowat D., Field M.,
RA Hackett A., Marynen P., Turner G., Gecz J.;
RT "Submicroscopic duplications of the hydroxysteroid dehydrogenase
RT HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental
RT retardation.";
RL Am. J. Hum. Genet. 82:432-443(2008).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which mediates
CC ubiquitination and subsequent proteasomal degradation of target
CC proteins. Regulates apoptosis by catalyzing the polyubiquitination
CC and degradation of MCL1. Mediates monoubiquitination of DNA
CC polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby
CC playing a role in base-excision repair. Also ubiquitinates the
CC p53/TP53 tumor suppressor and core histones including H1, H2A,
CC H2B, H3 and H4. Binds to an upstream initiator-like sequence in
CC the preprodynorphin gene. Regulates neural differentiation and
CC proliferation by catalyzing the polyubiquitination and degradation
CC of MYCN. May regulate abundance of CDC6 after DNA damage by
CC polyubiquitinating and targeting CDC6 to degradation.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with isoform p14ARF of CDKN2A which strongly
CC inhibits HUWE1 ubiquitin ligase activity. Interacts with MYCN,
CC POLB and CDC6.
CC -!- INTERACTION:
CC Q8N726:CDKN2A; NbExp=4; IntAct=EBI-625934, EBI-625922;
CC P04637:TP53; NbExp=3; IntAct=EBI-625934, EBI-366083;
CC Q13107:USP4; NbExp=4; IntAct=EBI-625934, EBI-723290;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Mainly expressed in
CC the cytoplasm of most tissues, except in the nucleus of
CC spermatogonia, primary spermatocytes and neuronal cells (By
CC similarity). Predominantly cytosolic or perinuclear in some
CC colorectal carcinoma cells.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=LASU1, Large structure of UREB1;
CC IsoId=Q7Z6Z7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q7Z6Z7-2; Sequence=VSP_011146;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q7Z6Z7-3; Sequence=VSP_015272;
CC -!- TISSUE SPECIFICITY: Weakly expressed in heart, brain and placenta
CC but not in other tissues. Expressed in a number of cell lines,
CC predominantly in those from colorectal carcinomas.
CC -!- DOMAIN: The HECT domain mediates inhibition of the transcriptional
CC activity of p53.
CC -!- PTM: Phosphorylated on tyrosine; phosphorylation is probably
CC required for its ability to inhibit TP53 transactivation (By
CC similarity).
CC -!- DISEASE: Mental retardation, X-linked, syndromic, Turner type
CC (MRXST) [MIM:300706]: A syndrome characterized by the association
CC of mental retardation with macrocephaly and variable contractures.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Mental retardation, X-linked 17 (MRX17) [MIM:300705]: A
CC disorder characterized by significantly below average general
CC intellectual functioning associated with impairments in adaptive
CC behavior and manifested during the developmental period.
CC Intellectual deficiency is the only primary symptom of non-
CC syndromic X-linked mental retardation, while syndromic mental
CC retardation presents with associated physical, neurological and/or
CC psychiatric manifestations. Note=The gene represented in this
CC entry is involved in disease pathogenesis. A chromosomal
CC microduplication involving HSD17B10 and HUWE1 has been found in
CC patients with mental retardation.
CC -!- SIMILARITY: Belongs to the UPL family. TOM1/PTR1 subfamily.
CC -!- SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein
CC ligase) domain.
CC -!- SIMILARITY: Contains 1 UBA domain.
CC -!- SIMILARITY: Contains 1 UIM (ubiquitin-interacting motif) repeat.
CC -!- SIMILARITY: Contains 1 WWE domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC62492.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAF28950.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=AAF28950.1; Type=Frameshift; Positions=4356;
CC Sequence=BAB13404.1; Type=Miscellaneous discrepancy; Note=Chimeric cDNA, contains the C-terminal part of ATP5I;
CC Sequence=BAC06833.1; Type=Frameshift; Positions=982, 1055;
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DR EMBL; AY772009; AAV90838.1; -; mRNA.
DR EMBL; DQ097177; AAY98258.1; -; mRNA.
DR EMBL; AY929612; AAX24125.1; -; mRNA.
DR EMBL; AL592046; CAI39580.1; -; Genomic_DNA.
DR EMBL; Z94044; CAI39580.1; JOINED; Genomic_DNA.
DR EMBL; Z97054; CAI39580.1; JOINED; Genomic_DNA.
DR EMBL; Z94044; CAI42354.1; -; Genomic_DNA.
DR EMBL; AL592046; CAI42354.1; JOINED; Genomic_DNA.
DR EMBL; Z97054; CAI42354.1; JOINED; Genomic_DNA.
DR EMBL; Z97054; CAI42654.1; -; Genomic_DNA.
DR EMBL; AL592046; CAI42654.1; JOINED; Genomic_DNA.
DR EMBL; Z94044; CAI42654.1; JOINED; Genomic_DNA.
DR EMBL; AB071605; BAC06833.1; ALT_FRAME; mRNA.
DR EMBL; AB002310; BAA20771.3; -; mRNA.
DR EMBL; AB046798; BAB13404.1; ALT_SEQ; mRNA.
DR EMBL; AF161390; AAF28950.1; ALT_SEQ; mRNA.
DR EMBL; BC002602; AAH02602.2; -; mRNA.
DR EMBL; BC063505; AAH63505.1; -; mRNA.
DR EMBL; AF057569; AAC62492.1; ALT_INIT; mRNA.
DR EMBL; CR456813; CAG33094.1; -; mRNA.
DR EMBL; AL162050; CAB82393.1; -; mRNA.
DR PIR; T47165; T47165.
DR RefSeq; NP_113584.3; NM_031407.6.
DR RefSeq; XP_005262022.1; XM_005261965.1.
DR RefSeq; XP_005262023.1; XM_005261966.1.
DR RefSeq; XP_005262024.1; XM_005261967.1.
DR RefSeq; XP_005262027.1; XM_005261970.1.
DR RefSeq; XP_005278018.1; XM_005277961.1.
DR RefSeq; XP_005278019.1; XM_005277962.1.
DR RefSeq; XP_005278020.1; XM_005277963.1.
DR RefSeq; XP_005278023.1; XM_005277966.1.
DR UniGene; Hs.136905; -.
DR PDB; 2EKK; NMR; -; A=1317-1356.
DR PDB; 3G1N; X-ray; 2.60 A; A/B=4005-4374.
DR PDB; 3H1D; X-ray; 1.89 A; A=3993-4374.
DR PDBsum; 2EKK; -.
DR PDBsum; 3G1N; -.
DR PDBsum; 3H1D; -.
DR ProteinModelPortal; Q7Z6Z7; -.
DR SMR; Q7Z6Z7; 1310-1356, 4000-4366.
DR DIP; DIP-34362N; -.
DR IntAct; Q7Z6Z7; 24.
DR MINT; MINT-1576525; -.
DR PhosphoSite; Q7Z6Z7; -.
DR DMDM; 73915353; -.
DR PaxDb; Q7Z6Z7; -.
DR PRIDE; Q7Z6Z7; -.
DR Ensembl; ENST00000262854; ENSP00000262854; ENSG00000086758.
DR Ensembl; ENST00000342160; ENSP00000340648; ENSG00000086758.
DR GeneID; 10075; -.
DR KEGG; hsa:10075; -.
DR UCSC; uc004dsp.4; human.
DR CTD; 10075; -.
DR GeneCards; GC0XM053575; -.
DR HGNC; HGNC:30892; HUWE1.
DR HPA; CAB022718; -.
DR HPA; HPA002548; -.
DR MIM; 300697; gene.
DR MIM; 300705; phenotype.
DR MIM; 300706; phenotype.
DR neXtProt; NX_Q7Z6Z7; -.
DR Orphanet; 85328; Intellectual deficit, X-linked, Turner type.
DR PharmGKB; PA128394567; -.
DR eggNOG; COG5021; -.
DR HOVERGEN; HBG080254; -.
DR KO; K10592; -.
DR OMA; GMTQEVG; -.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR ChiTaRS; HUWE1; human.
DR EvolutionaryTrace; Q7Z6Z7; -.
DR GeneWiki; HUWE1; -.
DR GenomeRNAi; 10075; -.
DR NextBio; 38085; -.
DR PRO; PR:Q7Z6Z7; -.
DR ArrayExpress; Q7Z6Z7; -.
DR Bgee; Q7Z6Z7; -.
DR Genevestigator; Q7Z6Z7; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0006284; P:base-excision repair; IMP:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0016574; P:histone ubiquitination; IDA:UniProtKB.
DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IDA:UniProtKB.
DR GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IBA:RefGenome.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR025527; DUF4414.
DR InterPro; IPR010309; E3_Ub_ligase_DUF908.
DR InterPro; IPR010314; E3_Ub_ligase_DUF913.
DR InterPro; IPR000569; HECT.
DR InterPro; IPR009060; UBA-like.
DR InterPro; IPR015940; UBA/transl_elong_EF1B_N_euk.
DR InterPro; IPR000449; UBA/Ts_N.
DR InterPro; IPR004170; WWE-dom.
DR Pfam; PF14377; DUF4414; 1.
DR Pfam; PF06012; DUF908; 1.
DR Pfam; PF06025; DUF913; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00627; UBA; 1.
DR Pfam; PF02825; WWE; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00165; UBA; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS50030; UBA; 1.
DR PROSITE; PS50330; UIM; FALSE_NEG.
DR PROSITE; PS50918; WWE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Chromosomal rearrangement;
KW Complete proteome; Cytoplasm; Differentiation; Disease mutation;
KW DNA damage; DNA repair; DNA-binding; Ligase; Mental retardation;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Ubl conjugation pathway.
FT CHAIN 1 4374 E3 ubiquitin-protein ligase HUWE1.
FT /FTId=PRO_0000120340.
FT DOMAIN 1316 1355 UBA.
FT REPEAT 1370 1389 UIM.
FT DOMAIN 1603 1680 WWE.
FT DOMAIN 4038 4374 HECT.
FT COMPBIAS 2295 2469 Glu-rich.
FT COMPBIAS 2427 2490 Asp-rich.
FT COMPBIAS 3483 3550 Thr-rich.
FT ACT_SITE 4341 4341 Glycyl thioester intermediate.
FT MOD_RES 1084 1084 Phosphoserine.
FT MOD_RES 1368 1368 Phosphoserine.
FT MOD_RES 1370 1370 Phosphoserine.
FT MOD_RES 1395 1395 Phosphoserine.
FT MOD_RES 1722 1722 Phosphothreonine.
FT MOD_RES 1907 1907 Phosphoserine.
FT MOD_RES 2362 2362 Phosphoserine.
FT MOD_RES 2365 2365 Phosphoserine.
FT MOD_RES 2391 2391 Phosphoserine.
FT MOD_RES 2595 2595 Phosphoserine.
FT MOD_RES 2619 2619 Phosphoserine.
FT MOD_RES 2751 2751 Phosphothreonine.
FT MOD_RES 2887 2887 Phosphoserine.
FT MOD_RES 2918 2918 Phosphoserine.
FT MOD_RES 3116 3116 Phosphoserine.
FT MOD_RES 3127 3127 Phosphoserine.
FT MOD_RES 3662 3662 Phosphoserine.
FT MOD_RES 3752 3752 Phosphoserine.
FT MOD_RES 3757 3757 Phosphoserine.
FT MOD_RES 3760 3760 Phosphoserine.
FT MOD_RES 3808 3808 Phosphoserine.
FT MOD_RES 3816 3816 Phosphoserine.
FT MOD_RES 3919 3919 Phosphoserine.
FT MOD_RES 3924 3924 Phosphothreonine.
FT MOD_RES 3927 3927 Phosphothreonine.
FT VAR_SEQ 982 990 Missing (in isoform 3).
FT /FTId=VSP_015272.
FT VAR_SEQ 3016 3031 Missing (in isoform 2).
FT /FTId=VSP_011146.
FT VARIANT 483 483 N -> S (in dbSNP:rs41307640).
FT /FTId=VAR_061986.
FT VARIANT 2981 2981 R -> H (in MRXS-Turner).
FT /FTId=VAR_045670.
FT VARIANT 4013 4013 R -> W (in MRXS-Turner).
FT /FTId=VAR_045671.
FT VARIANT 4187 4187 R -> C (in MRXS-Turner).
FT /FTId=VAR_045672.
FT MUTAGEN 4268 4268 Y->S: Loss of activity.
FT MUTAGEN 4341 4341 C->A,D: Loss of activity.
FT CONFLICT 1111 1111 K -> N (in Ref. 5; BAC06833).
FT CONFLICT 1124 1124 P -> L (in Ref. 1; AAV90838 and 5;
FT BAC06833).
FT CONFLICT 1190 1190 D -> H (in Ref. 5; BAC06833).
FT CONFLICT 1962 1962 Missing (in Ref. 6; BAA20771).
FT CONFLICT 2525 2525 H -> Y (in Ref. 5; BAC06833 and 9;
FT AAF28950).
FT CONFLICT 4022 4022 R -> L (in Ref. 10; AAH02602).
FT HELIX 1319 1329
FT HELIX 1332 1341
FT HELIX 1345 1353
FT HELIX 3994 4008
FT TURN 4009 4011
FT STRAND 4016 4021
FT HELIX 4023 4025
FT HELIX 4026 4034
FT HELIX 4041 4043
FT STRAND 4044 4050
FT HELIX 4061 4072
FT HELIX 4076 4078
FT STRAND 4080 4083
FT TURN 4085 4087
FT STRAND 4088 4093
FT HELIX 4095 4099
FT HELIX 4103 4120
FT HELIX 4130 4137
FT HELIX 4143 4145
FT HELIX 4146 4149
FT HELIX 4151 4162
FT HELIX 4165 4167
FT STRAND 4168 4170
FT STRAND 4172 4175
FT TURN 4176 4178
FT STRAND 4181 4183
FT HELIX 4186 4189
FT STRAND 4193 4197
FT TURN 4200 4202
FT HELIX 4203 4215
FT HELIX 4217 4219
FT HELIX 4220 4233
FT HELIX 4236 4239
FT HELIX 4244 4252
FT HELIX 4259 4264
FT STRAND 4266 4271
FT HELIX 4276 4287
FT HELIX 4290 4301
FT STRAND 4302 4304
FT HELIX 4311 4313
FT STRAND 4317 4320
FT STRAND 4323 4328
FT STRAND 4337 4339
FT HELIX 4340 4342
FT STRAND 4344 4348
FT HELIX 4353 4365
SQ SEQUENCE 4374 AA; 481891 MW; FA9D3A7712F6393B CRC64;
MKVDRTKLKK TPTEAPADCR ALIDKLKVCN DEQLLLELQQ IKTWNIGKCE LYHWVDLLDR
FDGILADAGQ TVENMSWMLV CDRPEREQLK MLLLAVLNFT ALLIEYSFSR HLYSSIEHLT
TLLASSDMQV VLAVLNLLYV FSKRSNYITR LGSDKRTPLL TRLQHLAESW GGKENGFGLA
ECCRDLHMMK YPPSATTLHF EFYADPGAEV KIEKRTTSNT LHYIHIEQLD KISESPSEIM
ESLTKMYSIP KDKQMLLFTH IRLAHGFSNH RKRLQAVQAR LHAISILVYS NALQESANSI
LYNGLIEELV DVLQITDKQL MEIKAASLRT LTSIVHLERT PKLSSIIDCT GTASYHGFLP
VLVRNCIQAM IDPSMDPYPH QFATALFSFL YHLASYDAGG EALVSCGMME ALLKVIKFLG
DEQDQITFVT RAVRVVDLIT NLDMAAFQSH SGLSIFIYRL EHEVDLCRKE CPFVIKPKIQ
RPNTTQEGEE METDMDGVQC IPQRAALLKS MLNFLKKAIQ DPAFSDGIRH VMDGSLPTSL
KHIISNAEYY GPSLFLLATE VVTVFVFQEP SLLSSLQDNG LTDVMLHALL IKDVPATREV
LGSLPNVFSA LCLNARGLQS FVQCQPFERL FKVLLSPDYL PAMRRRRSSD PLGDTASNLG
SAVDELMRHQ PTLKTDATTA IIKLLEEICN LGRDPKYICQ KPSIQKADGT ATAPPPRSNH
AAEEASSEDE EEEEVQAMQS FNSTQQNETE PNQQVVGTEE RIPIPLMDYI LNVMKFVESI
LSNNTTDDHC QEFVNQKGLL PLVTILGLPN LPIDFPTSAA CQAVAGVCKS ILTLSHEPKV
LQEGLLQLDS ILSSLEPLHR PIESPGGSVL LRELACAGNV ADATLSAQAT PLLHALTAAH
AYIMMFVHTC RVGQSEIRSI SVNQWGSQLG LSVLSKLSQL YCSLVWESTV LLSLCTPNSL
PSGCEFGQAD MQKLVPKDEK AGTTQGGKRS DGEQDGAAGS MDASTQGLLE GIGLDGDTLA
PMETDEPTAS DSKGKSKITP AMAARIKQIK PLLSASSRLG RALAELFGLL VKLCVGSPVR
QRRSHHAAST TTAPTPAARS TASALTKLLT KGLSWQPPPY TPTPRFRLTF FICSVGFTSP
MLFDERKYPY HLMLQKFLCS GGHNALFETF NWALSMGGKV PVSEGLEHSD LPDGTGEFLD
AWLMLVEKMV NPTTVLESPH SLPAKLPGGV QNFPQFSALR FLVVTQKAAF TCIKNLWNRK
PLKVYGGRMA ESMLAILCHI LRGEPVIRER LSKEKEGSRG EEDTGQEEGG SRREPQVNQQ
QLQQLMDMGF TREHAMEALL NTSTMEQATE YLLTHPPPIM GGVVRDLSMS EEDQMMRAIA
MSLGQDIPMD QRAESPEEVA CRKEEEERKA REKQEEEEAK CLEKFQDADP LEQDELHTFT
DTMLPGCFHL LDELPDTVYR VCDLIMTAIK RNGADYRDMI LKQVVNQVWE AADVLIKAAL
PLTTSDTKTV SEWISQMATL PQASNLATRI LLLTLLFEEL KLPCAWVVES SGILNVLIKL
LEVVQPCLQA AKEQKEVQTP KWITPVLLLI DFYEKTAISS KRRAQMTKYL QSNSNNWRWF
DDRSGRWCSY SASNNSTIDS AWKSGETSVR FTAGRRRYTV QFTTMVQVNE ETGNRRPVML
TLLRVPRLNK NSKNSNGQEL EKTLEESKEM DIKRKENKGN DTPLALESTN TEKETSLEET
KIGEILIQGL TEDMVTVLIR ACVSMLGVPV DPDTLHATLR LCLRLTRDHK YAMMFAELKS
TRMILNLTQS SGFNGFTPLV TLLLRHIIED PCTLRHTMEK VVRSAATSGA GSTTSGVVSG
SLGSREINYI LRVLGPAACR NPDIFTEVAN CCIRIALPAP RGSGTASDDE FENLRIKGPN
AVQLVKTTPL KPSPLPVIPD TIKEVIYDML NALAAYHAPE EADKSDPKPG VMTQEVGQLL
QDMGDDVYQQ YRSLTRQSSD FDTQSGFSIN SQVFAADGAS TETSASGTSQ GEASTPEESR
DGKKDKEGDR ASEEGKQKGK GSKPLMPTST ILRLLAELVR SYVGIATLIA NYSYTVGQSE
LIKEDCSVLA FVLDHLLPHT QNAEDKDTPA LARLFLASLA AAGSGTDAQV ALVNEVKAAL
GRALAMAEST EKHARLQAVM CIISTIMESC PSTSSFYSSA TAKTQHNGMN NIIRLFLKKG
LVNDLARVPH SLDLSSPNMA NTVNAALKPL ETLSRIVNQP SSLFGSKSAS SKNKSEQDAQ
GASQDSSSNQ QDPGEPGEAE VQEEDHDVTQ TEVADGDIMD GEAETDSVVI AGQPEVLSSQ
EMQVENELED LIDELLERDG GSGNSTIIVS RSGEDESQED VLMDEAPSNL SQASTLQANR
EDSMNILDPE DEEEHTQEED SSGSNEDEDD SQDEEEEEEE DEEDDQEDDE GEEGDEDDDD
DGSEMELDED YPDMNASPLV RFERFDREDD LIIEFDNMFS SATDIPPSPG NIPTTHPLMV
RHADHSSLTL GSGSSTTRLT QGIGRSQRTL RQLTANTGHT IHVHYPGNRQ PNPPLILQRL
LGPSAAADIL QLSSSLPLQS RGRARLLVGN DDVHIIARSD DELLDDFFHD QSTATSQAGT
LSSIPTALTR WTEECKVLDA ESMHDCVSVV KVSIVNHLEF LRDEELEERR EKRRKQLAEE
ETKITDKGKE DKENRDQSAQ CTASKSNDST EQNLSDGTPM PDSYPTTPSS TDAATSESKE
TLGTLQSSQQ QPTLPTPPAL GEVPQELQSP AGEGGSSTQL LMPVEPEELG PTRPSGEAET
TQMELSPAPT ITSLSPERAE DSDALTAVSS QLEGSPMDTS SLASCTLEEA VGDTSAAGSS
EQPRAGSSTP GDAPPAVAEV QGRSDGSGES AQPPEDSSPP ASSESSSTRD SAVAISGADS
RGILEEPLPS TSSEEEDPLA GISLPEGVDP SFLAALPDDI RREVLQNQLG IRPPTRTAPS
TNSSAPAVVG NPGVTEVSPE FLAALPPAIQ EEVLAQQRAE QQRRELAQNA SSDTPMDPVT
FIQTLPSDLR RSVLEDMEDS VLAVMPPDIA AEAQALRREQ EARQRQLMHE RLFGHSSTSA
LSAILRSPAF TSRLSGNRGV QYTRLAVQRG GTFQMGGSSS HNRPSGSNVD TLLRLRGRLL
LDHEALSCLL VLLFVDEPKL NTSRLHRVLR NLCYHAQTRH WVIRSLLSIL QRSSESELCI
ETPKLTTSEE KGKKSSKSCG SSSHENRPLD LLHKMESKSS NQLSWLSVSM DAALGCRTNI
FQIQRSGGRK HTEKHASGGS TVHIHPQAAP VVCRHVLDTL IQLAKVFPSH FTQQRTKETN
CESDRERGNK ACSPCSSQSS SSGICTDFWD LLVKLDNMNV SRKGKNSVKS VPVSAGGEGE
TSPYSLEASP LGQLMNMLSH PVIRRSSLLT EKLLRLLSLI SIALPENKVS EAQANSGSGA
SSTTTATSTT STTTTTAAST TPTPPTAPTP VTSAPALVAA TAISTIVVAA STTVTTPTTA
TTTVSISPTT KGSKSPAKVS DGGSSSTDFK MVSSGLTENQ LQLSVEVLTS HSCSEEGLED
AANVLLQLSR GDSGTRDTVL KLLLNGARHL GYTLCKQIGT LLAELREYNL EQQRRAQCET
LSPDGLPEEQ PQTTKLKGKM QSRFDMAENV VIVASQKRPL GGRELQLPSM SMLTSKTSTQ
KFFLRVLQVI IQLRDDTRRA NKKAKQTGRL GSSGLGSASS IQAAVRQLEA EADAIIQMVR
EGQRARRQQQ AATSESSQSE ASVRREESPM DVDQPSPSAQ DTQSIASDGT PQGEKEKEER
PPELPLLSEQ LSLDELWDML GECLKELEES HDQHAVLVLQ PAVEAFFLVH ATERESKPPV
RDTRESQLAH IKDEPPPLSP APLTPATPSS LDPFFSREPS SMHISSSLPP DTQKFLRFAE
THRTVLNQIL RQSTTHLADG PFAVLVDYIR VLDFDVKRKY FRQELERLDE GLRKEDMAVH
VRRDHVFEDS YRELHRKSPE EMKNRLYIVF EGEEGQDAGG LLREWYMIIS REMFNPMYAL
FRTSPGDRVT YTINPSSHCN PNHLSYFKFV GRIVAKAVYD NRLLECYFTR SFYKHILGKS
VRYTDMESED YHFYQGLVYL LENDVSTLGY DLTFSTEVQE FGVCEVRDLK PNGANILVTE
ENKKEYVHLV CQMRMTGAIR KQLAAFLEGF YEIIPKRLIS IFTEQELELL ISGLPTIDID
DLKSNTEYHK YQSNSIQIQW FWRALRSFDQ ADRAKFLQFV TGTSKVPLQG FAALEGMNGI
QKFQIHRDDR STDRLPSAHT CFNQLDLPAY ESFEKLRHML LLAIQECSEG FGLA
//
MIM
300697
*RECORD*
*FIELD* NO
300697
*FIELD* TI
*300697 HECT, UBA, AND WWE DOMAINS-CONTAINING PROTEIN 1; HUWE1
;;UPSTREAM REGULATORY ELEMENT-BINDING PROTEIN 1; UREB1;;
read moreURE-BINDING PROTEIN 1;;
LASU1;;
KIAA0312
*FIELD* TX
DESCRIPTION
The HUWE1 gene encodes an E3 ubiquitin ligase (summary by Froyen et al.,
2012).
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Nagase et al. (1997) cloned HUWE1, which they designated
KIAA0312. RT-PCR analysis detected low HUWE1 expression in all tissues
examined.
By database analysis, Liu et al. (2005) identified full-length human
HUWE1, which they called LASU1. The deduced 4,374-amino acids protein
has a calculated molecular mass of 481.9 kD. It has 2 N-terminal domains
similar to domains found in an S. cerevisiae HECT domain ligase, Tom1,
followed by a ubiquitin (191339)-associated (UBA) domain, a
ubiquitin-interacting motif (UIM), a WWE domain, and a C-terminal HECT
domain. The deduced full-length mouse Lasu1 protein contains 4,377 amino
acids.
Froyen et al. (2012) found expression of the Huwe1 gene in several mouse
tissues, including cortex, hippocampus, tongue, eye, kidney, liver,
adrenal gland, and fibroblasts.
GENE FUNCTION
Gu et al. (1994) found that a recombinant 310-amino acid Ureb1 protein
from rat brain specifically bound to the upstream regulatory element
(URE) in the promoter region of the rat preprodynorphin (PDYN; 131340)
gene. Tyrosine phosphorylation of Ureb1 increased transcription of a
reporter gene containing the URE.
Liu et al. (2005) showed that Lasu1 from bovine testis was a Ubc4
(UBE2D2; 602962)-dependent E3 ligase that ubiquitinated histones H1 (see
142709), H2A (see 613499), H2B (see 609904), H3 (see 602810), and H4
(see 602822) in vitro. Ubc4 isoform-1 and a testis-specific Ubc4 isoform
were the preferred E2s. Mass spectrometry and size analysis suggested
that Lasu1 functions as a monomer.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the HUWE1 gene
to chromosome X. Liu et al. (2005) mapped the mouse Huwe1 gene to
chromosome X.
CYTOGENETICS
Using X chromosome-specific array comparative genomic hybridization
(array CGH), Froyen et al. (2008) identified overlapping
microduplications of chromosome Xp11.22 in affected individuals from 6
unrelated families with nonsyndromic X-linked mental retardation (MRX17;
300705). Subsequent PCR analysis showed that the duplicated regions
varied from 0.4 to 0.8 Mb with a common minimal overlapping region that
contained 2 candidate genes, HSD17B10 (300256) and HUWE1, both of which
showed 2- to 5-fold overexpression in blood cells from affected
individuals.
Froyen et al. (2012) reported 6 additional families with nonsyndromic
X-linked mental retardation associated with duplications at Xp11.22
(300705). All patients had mild to moderate intellectual disability, but
some were able to attend school. Most patients had some additional
variable features, but these features were not consistent enough to form
a discernible pattern. All female carriers were phenotypically normal.
Microarray analysis identified 6 different but overlapping duplications
of chromosome Xp11.22 ranging in size from 0.4 to 1.0 Mb that segregated
with the phenotype. Combined with the cytogenetic data from the 6
families reported by Froyen et al. (2008), Froyen et al. (2012) found
that the common minimal region of overlap is 228 kb, which contains the
HUWE1 gene and excludes the HSD17B10 gene. Cell lines from patients
showed 2-fold increased expression of HUWE1, and studies in 4 female
carriers showed skewed X inactivation. The authors concluded that HUWE1
is the dosage-sensitive gene for which a 2-fold overexpression results
in cognitive impairment in males. All proximal and distal breakpoints
differed, excluding nonallelic homologous recombination (NAHR) as the
common mechanism. Junction and in silico analysis of breakpoint regions
showed that some contained repetitive sequences, palindromes, increased
GC content, or microhomology-mediated rearrangements suggestive of
replication-based duplication events. The duplication was shown to be
due to NAHR in only 1 family, whereas it was due to other mechanisms in
the other families; however, many breakpoints could not adequately be
studied. The findings indicated that the Xp11.22 region is prone to
recombination- and replication-based rearrangements.
MOLECULAR GENETICS
In affected individuals from 3 unrelated families with X-linked
syndromic mental retardation, Turner type (300706), Froyen et al. (2008)
identified a mutation in the HUWE1 gene (300697.0001-300697.0003). There
was some phenotypic variability between the families: 1 had associated
macrocephaly, whereas the others had mild and profound mental
retardation, respectively.
*FIELD* AV
.0001
MENTAL RETARDATION, X-LINKED, SYNDROMIC, TURNER TYPE
HUWE1, ARG4013TRP
In affected members of an Australian family with X-linked syndromic
mental retardation, Turner type (300706) (Turner et al., 1994), Froyen
et al. (2008) identified a 12037C-T transition in the HUWE1 gene,
resulting in an arg4013-to-trp (R4013W) substitution. The mutation
segregated with the disorder and was not identified in 750 control
individuals. Affected individuals and carrier females also had
macrocephaly.
.0002
MENTAL RETARDATION, X-LINKED, SYNDROMIC, TURNER TYPE
HUWE1, ARG2981HIS
In affected members of a family with MRXS-Turner (300706), Froyen et al.
(2008) identified an 8942G-A transition in the HUWE1 gene, resulting in
an arg2981-to-his (R2981H) substitution. The mutation segregated with
the disorder and was not identified in 750 control individuals.
.0003
MENTAL RETARDATION, X-LINKED, SYNDROMIC, TURNER TYPE
HUWE1, ARG4187CYS
In affected members of a family with MRXS-Turner (300706), Froyen et al.
(2008) identified a 12559C-T transition in the HUWE1 gene, resulting in
an arg4187-to-cys (R4187C) substitution. The mutation segregated with
the disorder and was not identified in 750 control individuals. Affected
individuals were profoundly retarded and showed variable contractures.
*FIELD* RF
1. Froyen, G.; Belet, S.; Martinez, F.; Santos-Reboucas, C. B.; Declercq,
M.; Verbeeck, J.; Donckers, L.; Berland, S.; Mayo, S.; Rosello, M.;
Pimentel, M. M. G.; Fintelman-Rodrigues, N.; and 12 others: Copy-number
gains of HUWE1 due to replication- and recombination-based rearrangements. Am.
J. Hum. Genet. 91: 252-264, 2012.
2. Froyen, G.; Corbett, M.; Vandewalle, J.; Jarvela, I.; Lawrence,
O.; Meldrum, C.; Bauters, M.; Govaerts, K.; Vandeleur, L.; Van Esch,
H.; Chelly, J.; Sanlaville, D.; and 22 others: Submicroscopic duplications
of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin
ligase HUWE1 are associated with mental retardation. Am. J. Hum.
Genet. 82: 432-443, 2008.
3. Gu, J.; Ren, K.; Dubner, R.; Iadarola, M. J.: Cloning of a DNA
binding protein that is a tyrosine kinase substrate and recognizes
an upstream initiator-like sequence in the promoter of the preprodynorphin
gene. Molec. Brain Res. 24: 77-88, 1994.
4. Liu, Z.; Oughtred, R.; Wing, S. S.: Characterization of E3-Histone,
a novel testis ubiquitin protein ligase which ubiquitinates histones. Molec.
Cell. Biol. 25: 2819-2831, 2005.
5. Nagase, T.; Ishikawa, K.; Nakajima, D.; Ohira, M.; Seki, N.; Miyajima,
N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of
the coding sequences of unidentified human genes. VII. The complete
sequences of 100 new cDNA clones from brain which can code for large
proteins in vitro. DNA Res. 4: 141-150, 1997.
6. Turner, F.; Gedeon, A.; Mulley, J.: X-linked mental retardation
with heterozygous expression and macrocephaly: pericentromeric gene
localization. Am. J. Med. Genet. 51: 575-580, 1994.
*FIELD* CN
Cassandra L. Kniffin - updated: 9/12/2012
Cassandra L. Kniffin - updated: 5/5/2008
*FIELD* CD
Patricia A. Hartz: 2/26/2008
*FIELD* ED
mcolton: 11/26/2013
mgross: 2/4/2013
mgross: 1/29/2013
mgross: 1/11/2013
carol: 9/12/2012
ckniffin: 9/12/2012
carol: 5/6/2008
ckniffin: 5/5/2008
mgross: 2/26/2008
*RECORD*
*FIELD* NO
300697
*FIELD* TI
*300697 HECT, UBA, AND WWE DOMAINS-CONTAINING PROTEIN 1; HUWE1
;;UPSTREAM REGULATORY ELEMENT-BINDING PROTEIN 1; UREB1;;
read moreURE-BINDING PROTEIN 1;;
LASU1;;
KIAA0312
*FIELD* TX
DESCRIPTION
The HUWE1 gene encodes an E3 ubiquitin ligase (summary by Froyen et al.,
2012).
CLONING
By sequencing clones obtained from a size-fractionated brain cDNA
library, Nagase et al. (1997) cloned HUWE1, which they designated
KIAA0312. RT-PCR analysis detected low HUWE1 expression in all tissues
examined.
By database analysis, Liu et al. (2005) identified full-length human
HUWE1, which they called LASU1. The deduced 4,374-amino acids protein
has a calculated molecular mass of 481.9 kD. It has 2 N-terminal domains
similar to domains found in an S. cerevisiae HECT domain ligase, Tom1,
followed by a ubiquitin (191339)-associated (UBA) domain, a
ubiquitin-interacting motif (UIM), a WWE domain, and a C-terminal HECT
domain. The deduced full-length mouse Lasu1 protein contains 4,377 amino
acids.
Froyen et al. (2012) found expression of the Huwe1 gene in several mouse
tissues, including cortex, hippocampus, tongue, eye, kidney, liver,
adrenal gland, and fibroblasts.
GENE FUNCTION
Gu et al. (1994) found that a recombinant 310-amino acid Ureb1 protein
from rat brain specifically bound to the upstream regulatory element
(URE) in the promoter region of the rat preprodynorphin (PDYN; 131340)
gene. Tyrosine phosphorylation of Ureb1 increased transcription of a
reporter gene containing the URE.
Liu et al. (2005) showed that Lasu1 from bovine testis was a Ubc4
(UBE2D2; 602962)-dependent E3 ligase that ubiquitinated histones H1 (see
142709), H2A (see 613499), H2B (see 609904), H3 (see 602810), and H4
(see 602822) in vitro. Ubc4 isoform-1 and a testis-specific Ubc4 isoform
were the preferred E2s. Mass spectrometry and size analysis suggested
that Lasu1 functions as a monomer.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the HUWE1 gene
to chromosome X. Liu et al. (2005) mapped the mouse Huwe1 gene to
chromosome X.
CYTOGENETICS
Using X chromosome-specific array comparative genomic hybridization
(array CGH), Froyen et al. (2008) identified overlapping
microduplications of chromosome Xp11.22 in affected individuals from 6
unrelated families with nonsyndromic X-linked mental retardation (MRX17;
300705). Subsequent PCR analysis showed that the duplicated regions
varied from 0.4 to 0.8 Mb with a common minimal overlapping region that
contained 2 candidate genes, HSD17B10 (300256) and HUWE1, both of which
showed 2- to 5-fold overexpression in blood cells from affected
individuals.
Froyen et al. (2012) reported 6 additional families with nonsyndromic
X-linked mental retardation associated with duplications at Xp11.22
(300705). All patients had mild to moderate intellectual disability, but
some were able to attend school. Most patients had some additional
variable features, but these features were not consistent enough to form
a discernible pattern. All female carriers were phenotypically normal.
Microarray analysis identified 6 different but overlapping duplications
of chromosome Xp11.22 ranging in size from 0.4 to 1.0 Mb that segregated
with the phenotype. Combined with the cytogenetic data from the 6
families reported by Froyen et al. (2008), Froyen et al. (2012) found
that the common minimal region of overlap is 228 kb, which contains the
HUWE1 gene and excludes the HSD17B10 gene. Cell lines from patients
showed 2-fold increased expression of HUWE1, and studies in 4 female
carriers showed skewed X inactivation. The authors concluded that HUWE1
is the dosage-sensitive gene for which a 2-fold overexpression results
in cognitive impairment in males. All proximal and distal breakpoints
differed, excluding nonallelic homologous recombination (NAHR) as the
common mechanism. Junction and in silico analysis of breakpoint regions
showed that some contained repetitive sequences, palindromes, increased
GC content, or microhomology-mediated rearrangements suggestive of
replication-based duplication events. The duplication was shown to be
due to NAHR in only 1 family, whereas it was due to other mechanisms in
the other families; however, many breakpoints could not adequately be
studied. The findings indicated that the Xp11.22 region is prone to
recombination- and replication-based rearrangements.
MOLECULAR GENETICS
In affected individuals from 3 unrelated families with X-linked
syndromic mental retardation, Turner type (300706), Froyen et al. (2008)
identified a mutation in the HUWE1 gene (300697.0001-300697.0003). There
was some phenotypic variability between the families: 1 had associated
macrocephaly, whereas the others had mild and profound mental
retardation, respectively.
*FIELD* AV
.0001
MENTAL RETARDATION, X-LINKED, SYNDROMIC, TURNER TYPE
HUWE1, ARG4013TRP
In affected members of an Australian family with X-linked syndromic
mental retardation, Turner type (300706) (Turner et al., 1994), Froyen
et al. (2008) identified a 12037C-T transition in the HUWE1 gene,
resulting in an arg4013-to-trp (R4013W) substitution. The mutation
segregated with the disorder and was not identified in 750 control
individuals. Affected individuals and carrier females also had
macrocephaly.
.0002
MENTAL RETARDATION, X-LINKED, SYNDROMIC, TURNER TYPE
HUWE1, ARG2981HIS
In affected members of a family with MRXS-Turner (300706), Froyen et al.
(2008) identified an 8942G-A transition in the HUWE1 gene, resulting in
an arg2981-to-his (R2981H) substitution. The mutation segregated with
the disorder and was not identified in 750 control individuals.
.0003
MENTAL RETARDATION, X-LINKED, SYNDROMIC, TURNER TYPE
HUWE1, ARG4187CYS
In affected members of a family with MRXS-Turner (300706), Froyen et al.
(2008) identified a 12559C-T transition in the HUWE1 gene, resulting in
an arg4187-to-cys (R4187C) substitution. The mutation segregated with
the disorder and was not identified in 750 control individuals. Affected
individuals were profoundly retarded and showed variable contractures.
*FIELD* RF
1. Froyen, G.; Belet, S.; Martinez, F.; Santos-Reboucas, C. B.; Declercq,
M.; Verbeeck, J.; Donckers, L.; Berland, S.; Mayo, S.; Rosello, M.;
Pimentel, M. M. G.; Fintelman-Rodrigues, N.; and 12 others: Copy-number
gains of HUWE1 due to replication- and recombination-based rearrangements. Am.
J. Hum. Genet. 91: 252-264, 2012.
2. Froyen, G.; Corbett, M.; Vandewalle, J.; Jarvela, I.; Lawrence,
O.; Meldrum, C.; Bauters, M.; Govaerts, K.; Vandeleur, L.; Van Esch,
H.; Chelly, J.; Sanlaville, D.; and 22 others: Submicroscopic duplications
of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin
ligase HUWE1 are associated with mental retardation. Am. J. Hum.
Genet. 82: 432-443, 2008.
3. Gu, J.; Ren, K.; Dubner, R.; Iadarola, M. J.: Cloning of a DNA
binding protein that is a tyrosine kinase substrate and recognizes
an upstream initiator-like sequence in the promoter of the preprodynorphin
gene. Molec. Brain Res. 24: 77-88, 1994.
4. Liu, Z.; Oughtred, R.; Wing, S. S.: Characterization of E3-Histone,
a novel testis ubiquitin protein ligase which ubiquitinates histones. Molec.
Cell. Biol. 25: 2819-2831, 2005.
5. Nagase, T.; Ishikawa, K.; Nakajima, D.; Ohira, M.; Seki, N.; Miyajima,
N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of
the coding sequences of unidentified human genes. VII. The complete
sequences of 100 new cDNA clones from brain which can code for large
proteins in vitro. DNA Res. 4: 141-150, 1997.
6. Turner, F.; Gedeon, A.; Mulley, J.: X-linked mental retardation
with heterozygous expression and macrocephaly: pericentromeric gene
localization. Am. J. Med. Genet. 51: 575-580, 1994.
*FIELD* CN
Cassandra L. Kniffin - updated: 9/12/2012
Cassandra L. Kniffin - updated: 5/5/2008
*FIELD* CD
Patricia A. Hartz: 2/26/2008
*FIELD* ED
mcolton: 11/26/2013
mgross: 2/4/2013
mgross: 1/29/2013
mgross: 1/11/2013
carol: 9/12/2012
ckniffin: 9/12/2012
carol: 5/6/2008
ckniffin: 5/5/2008
mgross: 2/26/2008
MIM
300705
*RECORD*
*FIELD* NO
300705
*FIELD* TI
#300705 MENTAL RETARDATION, X-LINKED 17; MRX17
;;MENTAL RETARDATION, X-LINKED 31; MRX31
read more*FIELD* TX
A number sign (#) is used with this entry because this form of
nonsyndromic X-linked mental retardation is caused by microduplications
of chromosome Xp11.22, which includes the HSD17B10 (300256) and HUWE1
(300697) genes. Increased dosage of HUWE1 is believed to be responsible
for the phenotype (Froyen et al., 2012).
Point mutations in the HSD17B10 and HUWE1 genes have been found to cause
syndromic forms of mental retardation, MRXS10 (300220) and MRXS-Turner
(300706), respectively.
CLINICAL FEATURES
Gedeon et al. (1994) reported a family in which 6 males spanning 3
generations had moderate mental retardation with slow speech development
inherited in an X-linked pattern. No significant common dysmorphic
features were noted.
Donnelly et al. (1996) reported a 4-generation family with multiple
males affected with global retardation that became apparent between ages
2 and 4 years. Inheritance was X-linked. Affected males had moderate
mental retardation without other obvious abnormalities.
Froyen et al. (2008) reported 4 families with X-linked mental
retardation. Affected individuals in 1 of the families, of Finnish
origin, had moderate mental retardation, speech difficulties,
dysarthria, and mild dysmorphic facies. Affected individuals in the
other families showed mild to moderate intellectual handicap with speech
delay and hyperactivity. One patient had moderate macroorchidism.
MAPPING
By linkage analysis of a family with X-linked mental retardation, Gedeon
et al. (1994) found linkage to the AR (313700) locus on chromosome
Xq11-q12 (maximum lod score of 2.40). Gedeon et al. (1994) termed the
locus MRX17.
By linkage analysis of a family with X-linked mental retardation,
Donnelly et al. (1996) identified a locus, termed MRX31, within a 12-cM
pericentromeric region between Xp11.23 (DXS1126) and Xq13.3 (DXS1124).
The highest lod score was 3.44 at the AR locus.
CYTOGENETICS
Using X chromosome-specific array comparative genomic hybridization
(array CGH), Froyen et al. (2008) identified overlapping
microduplications of chromosome Xp11.22 in affected individuals from 6
unrelated families with nonsyndromic X-linked mental retardation,
including the 2 families reported by Gedeon et al. (1994) and Donnelly
et al. (1996). Subsequent PCR analysis showed that the duplicated
regions varied from 0.4 to 0.8 Mb with a common minimal overlapping
region that contained 2 candidate genes, HSD17B10 and HUWE1, both of
which showed 2- to 5-fold overexpression in blood cells from affected
individuals.
Froyen et al. (2012) reported 6 additional families with nonsyndromic
X-linked mental retardation associated with duplications at Xp11.22. All
patients had mild to moderate intellectual disability, but some were
able to attend school. Most patients had some additional variable
features, but these features were not consistent enough to form a
discernible pattern. These variable features included facial
dysmorphism, urogenital anomalies, gastroesophageal reflux, and abnormal
gait. Some had EEG abnormalities and some had behavioral problems. All
female carriers were phenotypically normal. One of the families had
previously been reported by Madrigal et al. (2007). Microarray analysis
identified 6 different but overlapping duplications of chromosome
Xp11.22 ranging in size from 0.4 to 1.0 Mb that segregated with the
phenotype. Combined with the cytogenetic data from the 6 families
reported by Froyen et al. (2008), Froyen et al. (2012) found that the
common minimal region of overlap is 228 kb, which contains the HUWE1
gene and excludes the HSD17B10 gene. Cell lines from patients showed
2-fold increased expression of HUWE1, and studies in 4 female carriers
showed skewed X inactivation. The authors concluded that HUWE1 is the
dosage-sensitive gene for which a 2-fold overexpression results in
cognitive impairment in males. All proximal and distal breakpoints
differed, excluding nonallelic homologous recombination (NAHR) as the
common mechanism. Junction and in silico analysis of breakpoint regions
showed that some contained repetitive sequences, palindromes, increased
GC content, or microhomology-mediated rearrangements suggestive of
replication-based duplication events. The duplication was shown to be
due to NAHR in only 1 family, whereas it was due to other mechanisms in
the other families; however, many breakpoints could not adequately be
studied. The findings indicated that the Xp11.22 region is prone to
recombination- and replication-based rearrangements.
*FIELD* RF
1. Donnelly, A. J.; Partington, M. W.; Ryan, A. K.; Mulley, J. C.
: Regional localisation of two non-specific X-linked mental retardation
genes (MRX30 and MRX31). Am. J. Med. Genet. 64: 113-120, 1996.
2. Froyen, G.; Belet, S.; Martinez, F.; Santos-Reboucas, C. B.; Declercq,
M.; Verbeeck, J.; Donckers, L.; Berland, S.; Mayo, S.; Rosello, M.;
Pimentel, M. M. G.; Fintelman-Rodrigues, N.; and 12 others: Copy-number
gains of HUWE1 due to replication- and recombination-based rearrangements. Am.
J. Hum. Genet. 91: 252-264, 2012.
3. Froyen, G.; Corbett, M.; Vandewalle, J.; Jarvela, I.; Lawrence,
O.; Meldrum, C.; Bauters, M.; Govaerts, K.; Vandeleur, L.; Van Esch,
H.; Chelly, J.; Sanlaville, D.; and 22 others: Submicroscopic duplications
of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin
ligase HUWE1 are associated with mental retardation. Am. J. Hum.
Genet. 82: 432-443, 2008.
4. Gedeon, A.; Kerr, B.; Mulley, J.; Turner, G.: Pericentromeric
genes for non-specific X-linked mental retardation (MRX). Am. J.
Med. Genet. 51: 553-564, 1994.
5. Madrigal, I.; Rodriguez-Revenga, L.; Armengol, L.; Gonzalez, E.;
Rodriguez, B.; Badenas, C.; Sanchez, A.; Martinez, F.; Guitart, M.;
Fernandez-Carvajal, I.; Arranz, J. A.; Tejada, M. I.; Perez-Jurado,
L. A.; Estivill, X.; Mila, M.: X-chromosome tiling path array detection
of copy number variants in patients with chromosome X-linked mental
retardation. BMC Genomics 8: 443, 2007. Note: Electronic Article.
*FIELD* CN
Cassandra L. Kniffin - updated: 9/12/2012
*FIELD* CD
Cassandra L. Kniffin: 4/17/2008
*FIELD* ED
mcolton: 11/26/2013
carol: 9/12/2012
ckniffin: 9/12/2012
carol: 6/3/2008
carol: 5/6/2008
ckniffin: 5/5/2008
*RECORD*
*FIELD* NO
300705
*FIELD* TI
#300705 MENTAL RETARDATION, X-LINKED 17; MRX17
;;MENTAL RETARDATION, X-LINKED 31; MRX31
read more*FIELD* TX
A number sign (#) is used with this entry because this form of
nonsyndromic X-linked mental retardation is caused by microduplications
of chromosome Xp11.22, which includes the HSD17B10 (300256) and HUWE1
(300697) genes. Increased dosage of HUWE1 is believed to be responsible
for the phenotype (Froyen et al., 2012).
Point mutations in the HSD17B10 and HUWE1 genes have been found to cause
syndromic forms of mental retardation, MRXS10 (300220) and MRXS-Turner
(300706), respectively.
CLINICAL FEATURES
Gedeon et al. (1994) reported a family in which 6 males spanning 3
generations had moderate mental retardation with slow speech development
inherited in an X-linked pattern. No significant common dysmorphic
features were noted.
Donnelly et al. (1996) reported a 4-generation family with multiple
males affected with global retardation that became apparent between ages
2 and 4 years. Inheritance was X-linked. Affected males had moderate
mental retardation without other obvious abnormalities.
Froyen et al. (2008) reported 4 families with X-linked mental
retardation. Affected individuals in 1 of the families, of Finnish
origin, had moderate mental retardation, speech difficulties,
dysarthria, and mild dysmorphic facies. Affected individuals in the
other families showed mild to moderate intellectual handicap with speech
delay and hyperactivity. One patient had moderate macroorchidism.
MAPPING
By linkage analysis of a family with X-linked mental retardation, Gedeon
et al. (1994) found linkage to the AR (313700) locus on chromosome
Xq11-q12 (maximum lod score of 2.40). Gedeon et al. (1994) termed the
locus MRX17.
By linkage analysis of a family with X-linked mental retardation,
Donnelly et al. (1996) identified a locus, termed MRX31, within a 12-cM
pericentromeric region between Xp11.23 (DXS1126) and Xq13.3 (DXS1124).
The highest lod score was 3.44 at the AR locus.
CYTOGENETICS
Using X chromosome-specific array comparative genomic hybridization
(array CGH), Froyen et al. (2008) identified overlapping
microduplications of chromosome Xp11.22 in affected individuals from 6
unrelated families with nonsyndromic X-linked mental retardation,
including the 2 families reported by Gedeon et al. (1994) and Donnelly
et al. (1996). Subsequent PCR analysis showed that the duplicated
regions varied from 0.4 to 0.8 Mb with a common minimal overlapping
region that contained 2 candidate genes, HSD17B10 and HUWE1, both of
which showed 2- to 5-fold overexpression in blood cells from affected
individuals.
Froyen et al. (2012) reported 6 additional families with nonsyndromic
X-linked mental retardation associated with duplications at Xp11.22. All
patients had mild to moderate intellectual disability, but some were
able to attend school. Most patients had some additional variable
features, but these features were not consistent enough to form a
discernible pattern. These variable features included facial
dysmorphism, urogenital anomalies, gastroesophageal reflux, and abnormal
gait. Some had EEG abnormalities and some had behavioral problems. All
female carriers were phenotypically normal. One of the families had
previously been reported by Madrigal et al. (2007). Microarray analysis
identified 6 different but overlapping duplications of chromosome
Xp11.22 ranging in size from 0.4 to 1.0 Mb that segregated with the
phenotype. Combined with the cytogenetic data from the 6 families
reported by Froyen et al. (2008), Froyen et al. (2012) found that the
common minimal region of overlap is 228 kb, which contains the HUWE1
gene and excludes the HSD17B10 gene. Cell lines from patients showed
2-fold increased expression of HUWE1, and studies in 4 female carriers
showed skewed X inactivation. The authors concluded that HUWE1 is the
dosage-sensitive gene for which a 2-fold overexpression results in
cognitive impairment in males. All proximal and distal breakpoints
differed, excluding nonallelic homologous recombination (NAHR) as the
common mechanism. Junction and in silico analysis of breakpoint regions
showed that some contained repetitive sequences, palindromes, increased
GC content, or microhomology-mediated rearrangements suggestive of
replication-based duplication events. The duplication was shown to be
due to NAHR in only 1 family, whereas it was due to other mechanisms in
the other families; however, many breakpoints could not adequately be
studied. The findings indicated that the Xp11.22 region is prone to
recombination- and replication-based rearrangements.
*FIELD* RF
1. Donnelly, A. J.; Partington, M. W.; Ryan, A. K.; Mulley, J. C.
: Regional localisation of two non-specific X-linked mental retardation
genes (MRX30 and MRX31). Am. J. Med. Genet. 64: 113-120, 1996.
2. Froyen, G.; Belet, S.; Martinez, F.; Santos-Reboucas, C. B.; Declercq,
M.; Verbeeck, J.; Donckers, L.; Berland, S.; Mayo, S.; Rosello, M.;
Pimentel, M. M. G.; Fintelman-Rodrigues, N.; and 12 others: Copy-number
gains of HUWE1 due to replication- and recombination-based rearrangements. Am.
J. Hum. Genet. 91: 252-264, 2012.
3. Froyen, G.; Corbett, M.; Vandewalle, J.; Jarvela, I.; Lawrence,
O.; Meldrum, C.; Bauters, M.; Govaerts, K.; Vandeleur, L.; Van Esch,
H.; Chelly, J.; Sanlaville, D.; and 22 others: Submicroscopic duplications
of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin
ligase HUWE1 are associated with mental retardation. Am. J. Hum.
Genet. 82: 432-443, 2008.
4. Gedeon, A.; Kerr, B.; Mulley, J.; Turner, G.: Pericentromeric
genes for non-specific X-linked mental retardation (MRX). Am. J.
Med. Genet. 51: 553-564, 1994.
5. Madrigal, I.; Rodriguez-Revenga, L.; Armengol, L.; Gonzalez, E.;
Rodriguez, B.; Badenas, C.; Sanchez, A.; Martinez, F.; Guitart, M.;
Fernandez-Carvajal, I.; Arranz, J. A.; Tejada, M. I.; Perez-Jurado,
L. A.; Estivill, X.; Mila, M.: X-chromosome tiling path array detection
of copy number variants in patients with chromosome X-linked mental
retardation. BMC Genomics 8: 443, 2007. Note: Electronic Article.
*FIELD* CN
Cassandra L. Kniffin - updated: 9/12/2012
*FIELD* CD
Cassandra L. Kniffin: 4/17/2008
*FIELD* ED
mcolton: 11/26/2013
carol: 9/12/2012
ckniffin: 9/12/2012
carol: 6/3/2008
carol: 5/6/2008
ckniffin: 5/5/2008
MIM
300706
*RECORD*
*FIELD* NO
300706
*FIELD* TI
#300706 MENTAL RETARDATION, X-LINKED, SYNDROMIC, TURNER TYPE; MRXST
;;MENTAL RETARDATION AND MACROCEPHALY SYNDROME
read more*FIELD* TX
A number sign (#) is used with this entry because X-linked syndromic
mental retardation, Turner type, is caused by mutation in the HUWE1 gene
(300697).
A nonsyndromic form of X-linked mental retardation (300705), designated
MRX17 or MRX31, is caused by microduplications of chromosome Xp11.22,
which include the HUWE1 and HSD17B10 (300256) genes.
CLINICAL FEATURES
Turner et al. (1994) reported a large 5-generation family in which
several males had moderate to profound mental retardation consistent
with X-linked inheritance. Several carrier females had mild mental
retardation. Affected hemizygous males and heterozygous females had
macrocephaly. Variable features included limited extension of the elbows
and tapering fingers. There were 2 cases of holoprosencephaly in male
infants.
Froyen et al. (2008) reported 2 additional affected families. In 1
family, 3 males presented with moderate mental retardation. One was able
to work in a sheltered environment and learned to read. As a child he
had speech and language delay and clumsy motor skills. He was not
dysmorphic, but had a long face and pointed chin. His affected male
cousin had a similar phenotype. Neither had macrocephaly. An unrelated
family demonstrated severe to profound mental retardation. Two brothers
had no speech or language. One had flexion deformity of the knees, but
was able to walk. An affected uncle lived in a residential home and had
severe knee contractures. None had macrocephaly.
Johnson et al. (1998) reported a large family in which 10 males spanning
2 generations had moderate mental retardation. Two females, who were
sibs of affected males, were described as 'slow.' Four of 6 males
studied had macroorchidism, and 5 had macrocephaly, but 1 affected male
had normal testes. However, 2 unaffected males also had macroorchidism
and macrocephaly, suggesting that these traits may have segregated
independently in this family.
MAPPING
In their family with syndromic MRX, Turner et al. (1994) found linkage
to the pericentromeric region of the X chromosome, with a maximum lod
score of 3.31 at MAOB (309860) on Xp11.23, DXS991, and AR (313700) on
Xq11-q12. The candidate region spanned from DXS1068 to DXS1125.
By linkage analysis in a large family in which 10 males had moderate
mental retardation, Johnson et al. (1998) identified a 30-Mb region on
chromosome Xp11.2-q21.31 between markers DXS991 and DXS1002 (maximum lod
score of 2.96 at DXS1111, DXS566, and DXS986). The region overlapped
that identified by Turner et al. (1994).
MOLECULAR GENETICS
In affected individuals of the family reported by Turner et al. (1994),
Froyen et al. (2008) identified a mutation in the HUWE1 gene
(300697.0001). Affected individuals in 2 additional families were also
found to have mutations in the HUWE1 gene (300697.0002; 300697.0003).
*FIELD* RF
1. Froyen, G.; Corbett, M.; Vandewalle, J.; Jarvela, I.; Lawrence,
O.; Meldrum, C.; Bauters, M.; Govaerts, K.; Vandeleur, L.; Van Esch,
H.; Chelly, J.; Sanlaville, D.; and 22 others: Submicroscopic duplications
of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin
ligase HUWE1 are associated with mental retardation. Am. J. Hum.
Genet. 82: 432-443, 2008.
2. Johnson, J. P.; Nelson, R.; Schwartz, C. E.: A family with mental
retardation, variable macrocephaly and macro-orchidism, and linkage
to Xq12-q21. J. Med. Genet. 35: 1026-1030, 1998.
3. Turner, F.; Gedeon, A.; Mulley, J.: X-linked mental retardation
with heterozygous expression and macrocephaly: pericentromeric gene
localization. Am. J. Med. Genet. 51: 575-580, 1994.
*FIELD* CN
Cassandra L. Kniffin - updated: 10/26/2011
*FIELD* CD
Cassandra L. Kniffin: 4/18/2008
*FIELD* ED
carol: 12/05/2011
carol: 10/26/2011
ckniffin: 10/26/2011
carol: 6/3/2008
carol: 5/6/2008
ckniffin: 5/5/2008
*RECORD*
*FIELD* NO
300706
*FIELD* TI
#300706 MENTAL RETARDATION, X-LINKED, SYNDROMIC, TURNER TYPE; MRXST
;;MENTAL RETARDATION AND MACROCEPHALY SYNDROME
read more*FIELD* TX
A number sign (#) is used with this entry because X-linked syndromic
mental retardation, Turner type, is caused by mutation in the HUWE1 gene
(300697).
A nonsyndromic form of X-linked mental retardation (300705), designated
MRX17 or MRX31, is caused by microduplications of chromosome Xp11.22,
which include the HUWE1 and HSD17B10 (300256) genes.
CLINICAL FEATURES
Turner et al. (1994) reported a large 5-generation family in which
several males had moderate to profound mental retardation consistent
with X-linked inheritance. Several carrier females had mild mental
retardation. Affected hemizygous males and heterozygous females had
macrocephaly. Variable features included limited extension of the elbows
and tapering fingers. There were 2 cases of holoprosencephaly in male
infants.
Froyen et al. (2008) reported 2 additional affected families. In 1
family, 3 males presented with moderate mental retardation. One was able
to work in a sheltered environment and learned to read. As a child he
had speech and language delay and clumsy motor skills. He was not
dysmorphic, but had a long face and pointed chin. His affected male
cousin had a similar phenotype. Neither had macrocephaly. An unrelated
family demonstrated severe to profound mental retardation. Two brothers
had no speech or language. One had flexion deformity of the knees, but
was able to walk. An affected uncle lived in a residential home and had
severe knee contractures. None had macrocephaly.
Johnson et al. (1998) reported a large family in which 10 males spanning
2 generations had moderate mental retardation. Two females, who were
sibs of affected males, were described as 'slow.' Four of 6 males
studied had macroorchidism, and 5 had macrocephaly, but 1 affected male
had normal testes. However, 2 unaffected males also had macroorchidism
and macrocephaly, suggesting that these traits may have segregated
independently in this family.
MAPPING
In their family with syndromic MRX, Turner et al. (1994) found linkage
to the pericentromeric region of the X chromosome, with a maximum lod
score of 3.31 at MAOB (309860) on Xp11.23, DXS991, and AR (313700) on
Xq11-q12. The candidate region spanned from DXS1068 to DXS1125.
By linkage analysis in a large family in which 10 males had moderate
mental retardation, Johnson et al. (1998) identified a 30-Mb region on
chromosome Xp11.2-q21.31 between markers DXS991 and DXS1002 (maximum lod
score of 2.96 at DXS1111, DXS566, and DXS986). The region overlapped
that identified by Turner et al. (1994).
MOLECULAR GENETICS
In affected individuals of the family reported by Turner et al. (1994),
Froyen et al. (2008) identified a mutation in the HUWE1 gene
(300697.0001). Affected individuals in 2 additional families were also
found to have mutations in the HUWE1 gene (300697.0002; 300697.0003).
*FIELD* RF
1. Froyen, G.; Corbett, M.; Vandewalle, J.; Jarvela, I.; Lawrence,
O.; Meldrum, C.; Bauters, M.; Govaerts, K.; Vandeleur, L.; Van Esch,
H.; Chelly, J.; Sanlaville, D.; and 22 others: Submicroscopic duplications
of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin
ligase HUWE1 are associated with mental retardation. Am. J. Hum.
Genet. 82: 432-443, 2008.
2. Johnson, J. P.; Nelson, R.; Schwartz, C. E.: A family with mental
retardation, variable macrocephaly and macro-orchidism, and linkage
to Xq12-q21. J. Med. Genet. 35: 1026-1030, 1998.
3. Turner, F.; Gedeon, A.; Mulley, J.: X-linked mental retardation
with heterozygous expression and macrocephaly: pericentromeric gene
localization. Am. J. Med. Genet. 51: 575-580, 1994.
*FIELD* CN
Cassandra L. Kniffin - updated: 10/26/2011
*FIELD* CD
Cassandra L. Kniffin: 4/18/2008
*FIELD* ED
carol: 12/05/2011
carol: 10/26/2011
ckniffin: 10/26/2011
carol: 6/3/2008
carol: 5/6/2008
ckniffin: 5/5/2008