NEDD4_HUMAN
ID NEDD4_HUMAN Reviewed; 1319 AA.
AC P46934; A1KY35; A6ND72; A7MD29; B4E2R7; B7ZM59; B7ZM60; B9EGN5; D6RF89;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 4.
DT 03-AUG-2022, entry version 220.
DE RecName: Full=E3 ubiquitin-protein ligase NEDD4;
DE EC=2.3.2.26 {ECO:0000269|PubMed:17218260, ECO:0000269|PubMed:21399620};
DE AltName: Full=Cell proliferation-inducing gene 53 protein;
DE AltName: Full=HECT-type E3 ubiquitin transferase NEDD4;
DE AltName: Full=Neural precursor cell expressed developmentally down-regulated protein 4;
DE Short=NEDD-4;
GN Name=NEDD4; Synonyms=KIAA0093, NEDD4-1; ORFNames=PIG53;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], IDENTIFICATION BY MASS SPECTROMETRY,
RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH PTEN.
RX PubMed=17218260; DOI=10.1016/j.cell.2006.11.039;
RA Wang X., Trotman L.C., Koppie T., Alimonti A., Chen Z., Gao Z., Wang J.,
RA Erdjument-Bromage H., Tempst P., Cordon-Cardo C., Pandolfi P.P., Jiang X.;
RT "NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN.";
RL Cell 128:129-139(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND VARIANTS GLN-679
RP AND SER-698.
RC TISSUE=Bone marrow;
RX PubMed=7788527; DOI=10.1093/dnares/2.1.37;
RA Nagase T., Miyajima N., Tanaka A., Sazuka T., Seki N., Sato S., Tabata S.,
RA Ishikawa K., Kawarabayasi Y., Kotani H., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. III. The
RT coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 2:37-43(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND VARIANTS GLN-679
RP AND SER-698.
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND VARIANTS GLN-679
RP AND SER-698.
RA Kim J.W.;
RT "Identification of a human cell proliferation inducing gene.";
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Adipose tissue;
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., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANTS GLN-679 AND
RP SER-698.
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 4), AND VARIANTS
RP GLN-679 AND SER-698.
RC TISSUE=Brain, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP FUNCTION, AND INTERACTION WITH RAPGEF2.
RX PubMed=11598133; DOI=10.1074/jbc.m108373200;
RA Pham N., Rotin D.;
RT "Nedd4 regulates ubiquitination and stability of the guanine-nucleotide
RT exchange factor CNrasGEF.";
RL J. Biol. Chem. 276:46995-47003(2001).
RN [10]
RP INTERACTION WITH EBOLA VIRUS PROTEIN VP40.
RX PubMed=12559917; DOI=10.1016/s0022-2836(02)01406-7;
RA Timmins J., Schoehn G., Ricard-Blum S., Scianimanico S., Vernet T.,
RA Ruigrok R.W., Weissenhorn W.;
RT "Ebola virus matrix protein VP40 interaction with human cellular factors
RT Tsg101 and Nedd4.";
RL J. Mol. Biol. 326:493-502(2003).
RN [11]
RP INTERACTION WITH HTLV-1 MATRIX PROTEIN P19.
RX PubMed=14581525; DOI=10.1128/jvi.77.22.11882-11895.2003;
RA Bouamr F., Melillo J.A., Wang M.Q., Nagashima K., de Los Santos M.,
RA Rein A., Goff S.P.;
RT "PPPYVEPTAP motif is the late domain of human T-cell leukemia virus type 1
RT Gag and mediates its functional interaction with cellular proteins Nedd4
RT and Tsg101.";
RL J. Virol. 77:11882-11895(2003).
RN [12]
RP SUBCELLULAR LOCATION.
RX PubMed=18819914; DOI=10.1074/jbc.m804120200;
RA Putz U., Howitt J., Lackovic J., Foot N., Kumar S., Silke J., Tan S.S.;
RT "Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal
RT secretion of Nedd4 family proteins.";
RL J. Biol. Chem. 283:32621-32627(2008).
RN [13]
RP INTERACTION WITH HERPES SIMPLEX VIRUS 2 PROTEIN UL56.
RX PubMed=18353951; DOI=10.1128/jvi.02515-07;
RA Ushijima Y., Koshizuka T., Goshima F., Kimura H., Nishiyama Y.;
RT "Herpes simplex virus type 2 UL56 interacts with the ubiquitin ligase Nedd4
RT and increases its ubiquitination.";
RL J. Virol. 82:5220-5233(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-747, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [15]
RP FUNCTION, AND INTERACTION WITH ISG15.
RX PubMed=18305167; DOI=10.1073/pnas.0710629105;
RA Okumura A., Pitha P.M., Harty R.N.;
RT "ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by
RT blocking Nedd4 ligase activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:3974-3979(2008).
RN [16]
RP FUNCTION, AND INTERACTION WITH PTEN.
RX PubMed=18562292; DOI=10.1073/pnas.0803233105;
RA Fouladkou F., Landry T., Kawabe H., Neeb A., Lu C., Brose N., Stambolic V.,
RA Rotin D.;
RT "The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN
RT stability and localization.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:8585-8590(2008).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-747, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [18]
RP INTERACTION WITH ARRDC3.
RX PubMed=20559325; DOI=10.1038/embor.2010.80;
RA Nabhan J.F., Pan H., Lu Q.;
RT "Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to
RT mediate ubiquitination of the beta2-adrenergic receptor.";
RL EMBO Rep. 11:605-611(2010).
RN [19]
RP FUNCTION, AND INTERACTION WITH TNK2.
RX PubMed=20086093; DOI=10.1128/mcb.00013-10;
RA Lin Q., Wang J., Childress C., Sudol M., Carey D.J., Yang W.;
RT "HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal
RT growth factor (EGF)-induced degradation of EGF receptor and ACK.";
RL Mol. Cell. Biol. 30:1541-1554(2010).
RN [20]
RP INTERACTION WITH RAP2A AND TNIK.
RX PubMed=20159449; DOI=10.1016/j.neuron.2010.01.007;
RA Kawabe H., Neeb A., Dimova K., Young S.M. Jr., Takeda M.,
RA Katsurabayashi S., Mitkovski M., Malakhova O.A., Zhang D.E., Umikawa M.,
RA Kariya K., Goebbels S., Nave K.A., Rosenmund C., Jahn O., Rhee J.,
RA Brose N.;
RT "Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite
RT development.";
RL Neuron 65:358-372(2010).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
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., Buerckstuemmer T.,
RA 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 [23]
RP INTERACTION WITH FGFR1, AND FUNCTION IN UBIQUITINATION OF FGFR1.
RX PubMed=21765395; DOI=10.1038/emboj.2011.234;
RA Persaud A., Alberts P., Hayes M., Guettler S., Clarke I., Sicheri F.,
RA Dirks P., Ciruna B., Rotin D.;
RT "Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis
RT and function.";
RL EMBO J. 30:3259-3273(2011).
RN [24]
RP INTERACTION WITH ARRDC1; ARRDC2 AND ARRDC3, AND DOMAIN.
RX PubMed=21191027; DOI=10.1128/jvi.02045-10;
RA Rauch S., Martin-Serrano J.;
RT "Multiple interactions between the ESCRT machinery and arrestin-related
RT proteins: implications for PPXY-dependent budding.";
RL J. Virol. 85:3546-3556(2011).
RN [25]
RP INTERACTION WITH LAPTM4B.
RX PubMed=22096579; DOI=10.1371/journal.pone.0027478;
RA Milkereit R., Rotin D.;
RT "A role for the ubiquitin ligase Nedd4 in membrane sorting of LAPTM4
RT proteins.";
RL PLoS ONE 6:E27478-E27478(2011).
RN [26]
RP INTERACTION WITH ADRB2.
RX PubMed=23166351; DOI=10.1083/jcb.201208192;
RA Han S.O., Xiao K., Kim J., Wu J.H., Wisler J.W., Nakamura N.,
RA Freedman N.J., Shenoy S.K.;
RT "MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound
RT beta(2)-adrenergic receptors.";
RL J. Cell Biol. 199:817-830(2012).
RN [27]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2 (ISOFORM 4), CLEAVAGE OF
RP INITIATOR METHIONINE [LARGE SCALE ANALYSIS] (ISOFORM 4), AND IDENTIFICATION
RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [28]
RP INTERACTION WITH OTUD7B.
RX PubMed=22179831; DOI=10.1038/onc.2011.587;
RA Pareja F., Ferraro D.A., Rubin C., Cohen-Dvashi H., Zhang F., Aulmann S.,
RA Ben-Chetrit N., Pines G., Navon R., Crosetto N., Kostler W., Carvalho S.,
RA Lavi S., Schmitt F., Dikic I., Yakhini Z., Sinn P., Mills G.B., Yarden Y.;
RT "Deubiquitination of EGFR by Cezanne-1 contributes to cancer progression.";
RL Oncogene 31:4599-4608(2012).
RN [29]
RP INTERACTION WITH PRRG4.
RX PubMed=23873930; DOI=10.1074/jbc.m113.484683;
RA Yazicioglu M.N., Monaldini L., Chu K., Khazi F.R., Murphy S.L., Huang H.,
RA Margaritis P., High K.A.;
RT "Cellular localization and characterization of cytosolic binding partners
RT for Gla domain-containing proteins PRRG4 and PRRG2.";
RL J. Biol. Chem. 288:25908-25914(2013).
RN [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-742, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [31]
RP FUNCTION IN UBIQUITINATION OF BRAT1.
RX PubMed=25631046; DOI=10.1074/jbc.m114.613687;
RA Low L.H., Chow Y.L., Li Y., Goh C.P., Putz U., Silke J., Ouchi T.,
RA Howitt J., Tan S.S.;
RT "Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination
RT and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during
RT the DNA damage response.";
RL J. Biol. Chem. 290:7141-7150(2015).
RN [32]
RP INTERACTION WITH LDLRAD3.
RX PubMed=26854353; DOI=10.1021/acs.biochem.5b01218;
RA Noyes N.C., Hampton B., Migliorini M., Strickland D.K.;
RT "Regulation of Itch and Nedd4 E3 Ligase Activity and Degradation by
RT LRAD3.";
RL Biochemistry 55:1204-1213(2016).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1-152 (ISOFORM 4).
RG Structural genomics consortium (SGC);
RT "Crystal structure of the C2 domain of the E3 ubiquitin-protein ligase
RT Nedd4.";
RL Submitted (OCT-2007) to the PDB data bank.
RN [34]
RP STRUCTURE BY NMR OF 834-878, AND INTERACTION WITH EBOLA VIRUS MATRIX
RP PROTEIN VP40.
RA Iglesias-Bexiga M.;
RT "Human NEDD4 3rd WW domain complex with ebola Zaire virus matrix protein
RT VP40 derived peptide.";
RL Submitted (OCT-2009) to the PDB data bank.
RN [35]
RP STRUCTURE BY NMR OF 834-878.
RA Iglesias-Bexiga M., Luque I., Macias M.;
RT "Human NEDD4 3rd WW domain complex with human T-cell leukemia virus GAP-Pro
RT polyprotein derived peptide.";
RL Submitted (OCT-2009) to the PDB data bank.
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 938-1319 IN COMPLEX WITH
RP UBIQUITIN, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=21399620; DOI=10.1038/embor.2011.21;
RA Maspero E., Mari S., Valentini E., Musacchio A., Fish A., Pasqualato S.,
RA Polo S.;
RT "Structure of the HECT:ubiquitin complex and its role in ubiquitin chain
RT elongation.";
RL EMBO Rep. 12:342-349(2011).
RN [37]
RP STRUCTURE BY NMR OF 838-877 IN COMPLEX WITH SCNN1A PEPTIDE, AND INTERACTION
RP WITH SCNN1A.
RX PubMed=23665454; DOI=10.1016/j.bbapap.2013.04.031;
RA Bobby R., Medini K., Neudecker P., Lee T.V., Brimble M.A., McDonald F.J.,
RA Lott J.S., Dingley A.J.;
RT "Structure and dynamics of human Nedd4-1 WW3 in complex with the alphaENaC
RT PY motif.";
RL Biochim. Biophys. Acta 1834:1632-1641(2013).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (2.51 ANGSTROMS) OF 938-1319 IN COMPLEX WITH
RP UBIQUITIN, FUNCTION, AND PATHWAY.
RX PubMed=23644597; DOI=10.1038/nsmb.2566;
RA Maspero E., Valentini E., Mari S., Cecatiello V., Soffientini P.,
RA Pasqualato S., Polo S.;
RT "Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis
RT for catalytic priming.";
RL Nat. Struct. Mol. Biol. 20:696-701(2013).
RN [39]
RP X-RAY CRYSTALLOGRAPHY (1.10 ANGSTROMS) OF 841-874 IN COMPLEX WITH ARRDC3
RP PEPTIDE, INTERACTION WITH ARRDC3, AND MUTAGENESIS OF TRP-795; TRP-868 AND
RP TRP-920.
RX PubMed=24379409; DOI=10.1074/jbc.m113.527473;
RA Qi S., O'Hayre M., Gutkind J.S., Hurley J.H.;
RT "Structural and biochemical basis for ubiquitin ligase recruitment by
RT arrestin-related domain-containing protein-3 (ARRDC3).";
RL J. Biol. Chem. 289:4743-4752(2014).
RN [40]
RP VARIANT [LARGE SCALE ANALYSIS] HIS-627.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an
CC E2 ubiquitin-conjugating enzyme in the form of a thioester and then
CC directly transfers the ubiquitin to targeted substrates. Specifically
CC ubiquitinates 'Lys-63' in target proteins (PubMed:23644597). Involved
CC in the pathway leading to the degradation of VEGFR-2/KDFR,
CC independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R
CC at multiple sites, thus leading to receptor internalization and
CC degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor
CC internalization and degradation in lysosomes. Promotes ubiquitination
CC of RAPGEF2. According to PubMed:18562292 the direct link between NEDD4
CC and PTEN regulation through polyubiquitination described in
CC PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4
CC intracellular domain E4ICD. Involved in the budding of many viruses.
CC Part of a signaling complex composed of NEDD4, RAP2A and TNIK which
CC regulates neuronal dendrite extension and arborization during
CC development. Ubiquitinates TNK2 and regulates EGF-induced degradation
CC of EGFR and TNF2. Ubiquitinates BRAT1 and this ubiquitination is
CC enhanced in the presence of NDFIP1 (PubMed:25631046).
CC {ECO:0000269|PubMed:11598133, ECO:0000269|PubMed:17218260,
CC ECO:0000269|PubMed:18305167, ECO:0000269|PubMed:18562292,
CC ECO:0000269|PubMed:20086093, ECO:0000269|PubMed:21399620,
CC ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:23644597,
CC ECO:0000269|PubMed:25631046}.
CC -!- FUNCTION: (Microbial infection) Involved in the ubiquitination of Ebola
CC virus protein VP40 which plays a role in viral budding.
CC {ECO:0000269|PubMed:12559917}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.26; Evidence={ECO:0000269|PubMed:17218260,
CC ECO:0000269|PubMed:21399620};
CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC {ECO:0000250}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:23644597}.
CC -!- SUBUNIT: Interacts with UBE2D2. Binds SCNN1A, SCNN1B and SCNN1G. Binds,
CC in vitro, through the WW2 and WW3 domains, to neural isoforms of ENAH
CC that contain the PPSY motif. Interacts with BEAN1, LITAF, RNF11, WBP1,
CC WBP2, PMEPAI and PRRG2 (By similarity). Interacts with NDFIP1 and
CC NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and
CC may induce its recruitment to exosomes (By similarity). Interaction
CC with PTEN is questionable according to PubMed:18562292. Interacts (via
CC C2 domain) with GRB10 (via SH2 domain). Interacts with ERBB4 (By
CC similarity). Interacts with TNIK; the interaction is direct, allows the
CC TNIK-dependent recruitment of RAP2A and its ubiquitination by NEDD4.
CC Interacts (via WW3 domain) with TNK2; EGF promotes this interaction.
CC Interacts (via WW3 domain) with FGFR1 (via C-terminus). Interacts with
CC OTUD7B. Interacts with ISG15. Interacts (via WW domain) with RAPGEF2;
CC this interaction leads to ubiquitination and degradation via the
CC proteasome pathway. Interacts (via WW domains) with ARRDC3 (via PPXY
CC motifs) (PubMed:20559325, PubMed:24379409). Interacts with LAPTM4B; may
CC play a role in the lysosomal sorting of LAPTM4B (PubMed:22096579).
CC Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3
CC (PubMed:21191027). Interacts with ZBTB7B (By similarity). Interacts
CC with PRRG4 (via cytoplasmic domain) (PubMed:23873930). Interacts
CC directly with LDLRAD3; this interaction promotes NEDD4 auto-
CC ubiquitination. Interacts with ADRB2 (PubMed:23166351). {ECO:0000250,
CC ECO:0000250|UniProtKB:P46935, ECO:0000269|PubMed:11598133,
CC ECO:0000269|PubMed:17218260, ECO:0000269|PubMed:18305167,
CC ECO:0000269|PubMed:18562292, ECO:0000269|PubMed:20086093,
CC ECO:0000269|PubMed:20159449, ECO:0000269|PubMed:20559325,
CC ECO:0000269|PubMed:21191027, ECO:0000269|PubMed:21399620,
CC ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:22096579,
CC ECO:0000269|PubMed:22179831, ECO:0000269|PubMed:23166351,
CC ECO:0000269|PubMed:23665454, ECO:0000269|PubMed:23873930,
CC ECO:0000269|PubMed:24379409}.
CC -!- SUBUNIT: (Microbial infection) Interacts with viral proteins that
CC contain a late-budding motif P-P-P-Y. This interaction is essential for
CC viral particle budding of many retroviruses, like HTLV-1 Gag and MLV
CC Gag. Interacts with Herpes simplex virus 2 (HHV-2) protein UL56; this
CC interaction induces NEDD4 degradation (PubMed:18353951). Interacts with
CC Ebola virus protein VP40 (PubMed:12559917).
CC {ECO:0000269|PubMed:12559917, ECO:0000269|PubMed:14581525,
CC ECO:0000269|PubMed:18353951}.
CC -!- INTERACTION:
CC P46934; Q96B67: ARRDC3; NbExp=3; IntAct=EBI-726944, EBI-2875665;
CC P46934; P54259: ATN1; NbExp=2; IntAct=EBI-726944, EBI-945980;
CC P46934; Q9H305: CDIP1; NbExp=2; IntAct=EBI-726944, EBI-2876678;
CC P46934; P00533: EGFR; NbExp=3; IntAct=EBI-726944, EBI-297353;
CC P46934; P11362: FGFR1; NbExp=26; IntAct=EBI-726944, EBI-1028277;
CC P46934; O95166: GABARAP; NbExp=6; IntAct=EBI-726944, EBI-712001;
CC P46934; Q9H0R8: GABARAPL1; NbExp=6; IntAct=EBI-726944, EBI-746969;
CC P46934; P60520: GABARAPL2; NbExp=6; IntAct=EBI-726944, EBI-720116;
CC P46934; Q99732: LITAF; NbExp=7; IntAct=EBI-726944, EBI-725647;
CC P46934; Q9GZQ8: MAP1LC3B; NbExp=3; IntAct=EBI-726944, EBI-373144;
CC P46934; Q14686: NCOA6; NbExp=2; IntAct=EBI-726944, EBI-78670;
CC P46934; Q14934: NFATC4; NbExp=2; IntAct=EBI-726944, EBI-3905796;
CC P46934; Q6GQQ9: OTUD7B; NbExp=2; IntAct=EBI-726944, EBI-527784;
CC P46934; Q9UKN5: PRDM4; NbExp=2; IntAct=EBI-726944, EBI-2803427;
CC P46934; Q9BZD6: PRRG4; NbExp=3; IntAct=EBI-726944, EBI-3918643;
CC P46934; P60484: PTEN; NbExp=4; IntAct=EBI-726944, EBI-696162;
CC P46934; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-726944, EBI-396669;
CC P46934; P37088: SCNN1A; NbExp=3; IntAct=EBI-726944, EBI-7845444;
CC P46934; P51168: SCNN1B; NbExp=5; IntAct=EBI-726944, EBI-2547187;
CC P46934; Q8IV31: TMEM139; NbExp=2; IntAct=EBI-726944, EBI-7238458;
CC P46934; Q8N4L1: TMEM151A; NbExp=2; IntAct=EBI-726944, EBI-25600031;
CC P46934; O15417: TNRC18; NbExp=2; IntAct=EBI-726944, EBI-2824620;
CC P46934; Q96PN7: TRERF1; NbExp=2; IntAct=EBI-726944, EBI-3505166;
CC P46934; P0CG47: UBB; NbExp=2; IntAct=EBI-726944, EBI-413034;
CC P46934-3; Q9H0R8: GABARAPL1; NbExp=3; IntAct=EBI-11980721, EBI-746969;
CC P46934-3; P60520: GABARAPL2; NbExp=3; IntAct=EBI-11980721, EBI-720116;
CC P46934-3; A0A024R8L2: hCG_1987119; NbExp=3; IntAct=EBI-11980721, EBI-14103818;
CC P46934-3; O15160: POLR1C; NbExp=3; IntAct=EBI-11980721, EBI-1055079;
CC P46934-3; Q6ZSJ9: SHISA6; NbExp=3; IntAct=EBI-11980721, EBI-12037847;
CC P46934-3; P84022: SMAD3; NbExp=3; IntAct=EBI-11980721, EBI-347161;
CC P46934-3; Q05BL1: TP53BP2; NbExp=3; IntAct=EBI-11980721, EBI-11952721;
CC P46934-3; P0DTC2: S; Xeno; NbExp=2; IntAct=EBI-11980721, EBI-25474821;
CC P46934-4; Q9HAU4: SMURF2; NbExp=2; IntAct=EBI-16129814, EBI-396727;
CC P46934-4; P62990: UBC; Xeno; NbExp=2; IntAct=EBI-16129814, EBI-413053;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane
CC {ECO:0000250}; Peripheral membrane protein {ECO:0000250}.
CC Note=Recruited to the plasma membrane by GRB10. Once complexed with
CC GRB10 and IGF1R, follows IGF1R internalization, remaining associated
CC with early endosomes. Uncouples from IGF1R-containing endosomes before
CC the sorting of the receptor to the lysosomal compartment (By
CC similarity). May be recruited to exosomes by NDFIP1. {ECO:0000250,
CC ECO:0000269|PubMed:18819914}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P46934-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P46934-2; Sequence=VSP_038259;
CC Name=3;
CC IsoId=P46934-3; Sequence=VSP_038258;
CC Name=4;
CC IsoId=P46934-4; Sequence=VSP_038256, VSP_038257;
CC -!- DOMAIN: The WW domains mediate interaction with PPxY motif-containing
CC proteins (PubMed:21191027). The WW domains mediate interaction with
CC LITAF, RNF11, WBP1, WBP2, PMEPAI, NDFIP1 and PRRG2 (By similarity).
CC {ECO:0000250, ECO:0000269|PubMed:21191027}.
CC -!- PTM: Auto-ubiquitinated. {ECO:0000250}.
CC -!- MISCELLANEOUS: A cysteine residue is required for ubiquitin-thioester
CC formation.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA07655.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; D42055; BAA07655.1; ALT_INIT; mRNA.
DR EMBL; AK304394; BAG65229.1; -; mRNA.
DR EMBL; AY550969; AAT52215.1; -; mRNA.
DR EMBL; AL832063; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC009997; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC039057; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471082; EAW77495.1; -; Genomic_DNA.
DR EMBL; BC136605; AAI36606.1; -; mRNA.
DR EMBL; BC144284; AAI44285.1; -; mRNA.
DR EMBL; BC144285; AAI44286.1; -; mRNA.
DR EMBL; BC152452; AAI52453.1; -; mRNA.
DR EMBL; BC152562; AAI52563.1; -; mRNA.
DR CCDS; CCDS10156.1; -. [P46934-3]
DR CCDS; CCDS45265.1; -. [P46934-4]
DR CCDS; CCDS61643.1; -. [P46934-2]
DR CCDS; CCDS61644.1; -. [P46934-1]
DR RefSeq; NP_001271267.1; NM_001284338.1. [P46934-1]
DR RefSeq; NP_001271268.1; NM_001284339.1. [P46934-2]
DR RefSeq; NP_001271269.1; NM_001284340.1.
DR RefSeq; NP_001316141.1; NM_001329212.1.
DR RefSeq; NP_006145.2; NM_006154.3. [P46934-4]
DR RefSeq; NP_940682.2; NM_198400.3. [P46934-3]
DR PDB; 2KPZ; NMR; -; A=834-878.
DR PDB; 2KQ0; NMR; -; A=834-878.
DR PDB; 2M3O; NMR; -; W=838-877.
DR PDB; 2XBB; X-ray; 2.68 A; A/B=938-1319.
DR PDB; 2XBF; X-ray; 2.50 A; A=938-1319.
DR PDB; 3B7Y; X-ray; 1.80 A; A/B=517-571.
DR PDB; 4BBN; X-ray; 2.51 A; A=938-1319.
DR PDB; 4BE8; X-ray; 3.00 A; A=938-1319.
DR PDB; 4N7F; X-ray; 1.10 A; A/B=841-874.
DR PDB; 4N7H; X-ray; 1.70 A; A=840-872.
DR PDB; 5AHT; NMR; -; A=838-877.
DR PDB; 5C7J; X-ray; 3.00 A; A/B=939-1319.
DR PDB; 5C91; X-ray; 2.44 A; A=938-1312.
DR PDBsum; 2KPZ; -.
DR PDBsum; 2KQ0; -.
DR PDBsum; 2M3O; -.
DR PDBsum; 2XBB; -.
DR PDBsum; 2XBF; -.
DR PDBsum; 3B7Y; -.
DR PDBsum; 4BBN; -.
DR PDBsum; 4BE8; -.
DR PDBsum; 4N7F; -.
DR PDBsum; 4N7H; -.
DR PDBsum; 5AHT; -.
DR PDBsum; 5C7J; -.
DR PDBsum; 5C91; -.
DR AlphaFoldDB; P46934; -.
DR SMR; P46934; -.
DR BioGRID; 110811; 470.
DR CORUM; P46934; -.
DR DIP; DIP-29815N; -.
DR ELM; P46934; -.
DR IntAct; P46934; 276.
DR MINT; P46934; -.
DR STRING; 9606.ENSP00000424827; -.
DR ChEMBL; CHEMBL3621023; -.
DR TCDB; 8.A.30.1.2; the nedd4-family interacting protein-2 (nedd4) family.
DR iPTMnet; P46934; -.
DR PhosphoSitePlus; P46934; -.
DR BioMuta; NEDD4; -.
DR DMDM; 313104311; -.
DR EPD; P46934; -.
DR jPOST; P46934; -.
DR MassIVE; P46934; -.
DR MaxQB; P46934; -.
DR PaxDb; P46934; -.
DR PeptideAtlas; P46934; -.
DR PRIDE; P46934; -.
DR ProteomicsDB; 55768; -. [P46934-1]
DR ProteomicsDB; 55769; -. [P46934-2]
DR ProteomicsDB; 55770; -. [P46934-3]
DR ProteomicsDB; 55771; -. [P46934-4]
DR Antibodypedia; 25114; 306 antibodies from 39 providers.
DR CPTC; P46934; 3 antibodies.
DR DNASU; 4734; -.
DR Ensembl; ENST00000338963.6; ENSP00000345530.2; ENSG00000069869.17. [P46934-3]
DR Ensembl; ENST00000435532.8; ENSP00000410613.3; ENSG00000069869.17. [P46934-4]
DR Ensembl; ENST00000506154.1; ENSP00000422705.1; ENSG00000069869.17. [P46934-2]
DR Ensembl; ENST00000508342.5; ENSP00000424827.1; ENSG00000069869.17. [P46934-1]
DR GeneID; 4734; -.
DR KEGG; hsa:4734; -.
DR MANE-Select; ENST00000435532.8; ENSP00000410613.3; NM_006154.4; NP_006145.2. [P46934-4]
DR UCSC; uc002adi.5; human. [P46934-1]
DR CTD; 4734; -.
DR DisGeNET; 4734; -.
DR GeneCards; NEDD4; -.
DR HGNC; HGNC:7727; NEDD4.
DR HPA; ENSG00000069869; Tissue enhanced (skeletal muscle, tongue).
DR MIM; 602278; gene.
DR neXtProt; NX_P46934; -.
DR OpenTargets; ENSG00000069869; -.
DR PharmGKB; PA31533; -.
DR VEuPathDB; HostDB:ENSG00000069869; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00940000158905; -.
DR HOGENOM; CLU_002173_3_0_1; -.
DR InParanoid; P46934; -.
DR OMA; PPYQDYE; -.
DR OrthoDB; 271539at2759; -.
DR PhylomeDB; P46934; -.
DR TreeFam; TF323658; -.
DR BRENDA; 2.3.2.26; 2681.
DR PathwayCommons; P46934; -.
DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
DR Reactome; R-HSA-1253288; Downregulation of ERBB4 signaling.
DR Reactome; R-HSA-8948747; Regulation of PTEN localization.
DR Reactome; R-HSA-8948751; Regulation of PTEN stability and activity.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; P46934; -.
DR SIGNOR; P46934; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 4734; 11 hits in 1118 CRISPR screens.
DR ChiTaRS; NEDD4; human.
DR EvolutionaryTrace; P46934; -.
DR GeneWiki; NEDD4; -.
DR GenomeRNAi; 4734; -.
DR Pharos; P46934; Tchem.
DR PRO; PR:P46934; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; P46934; protein.
DR Bgee; ENSG00000069869; Expressed in colonic epithelium and 167 other tissues.
DR ExpressionAtlas; P46934; baseline and differential.
DR Genevisible; P46934; HS.
DR GO; GO:0016327; C:apicolateral plasma membrane; TAS:BHF-UCL.
DR GO; GO:0005938; C:cell cortex; IDA:BHF-UCL.
DR GO; GO:0000785; C:chromatin; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; ISS:BHF-UCL.
DR GO; GO:0043197; C:dendritic spine; IBA:GO_Central.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:ARUK-UCL.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISS:BHF-UCL.
DR GO; GO:0031698; F:beta-2 adrenergic receptor binding; IDA:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; IPI:ARUK-UCL.
DR GO; GO:0050815; F:phosphoserine residue binding; ISS:BHF-UCL.
DR GO; GO:0050816; F:phosphothreonine residue binding; ISS:BHF-UCL.
DR GO; GO:0070064; F:proline-rich region binding; IMP:BHF-UCL.
DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB.
DR GO; GO:0070063; F:RNA polymerase binding; IPI:BHF-UCL.
DR GO; GO:0019871; F:sodium channel inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0043130; F:ubiquitin binding; IDA:BHF-UCL.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:ARUK-UCL.
DR GO; GO:0034644; P:cellular response to UV; IMP:BHF-UCL.
DR GO; GO:0044111; P:formation of structure involved in a symbiotic process; IMP:UniProtKB.
DR GO; GO:0042921; P:glucocorticoid receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0007041; P:lysosomal transport; IDA:UniProtKB.
DR GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0010766; P:negative regulation of sodium ion transport; IDA:UniProtKB.
DR GO; GO:0010768; P:negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage; IMP:BHF-UCL.
DR GO; GO:0030948; P:negative regulation of vascular endothelial growth factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0007528; P:neuromuscular junction development; IBA:GO_Central.
DR GO; GO:0031175; P:neuron projection development; IEP:BHF-UCL.
DR GO; GO:0046824; P:positive regulation of nucleocytoplasmic transport; IDA:BHF-UCL.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IMP:BHF-UCL.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:MGI.
DR GO; GO:0050847; P:progesterone receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0006622; P:protein targeting to lysosome; IPI:ARUK-UCL.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0032801; P:receptor catabolic process; IDA:UniProtKB.
DR GO; GO:0031623; P:receptor internalization; IDA:UniProtKB.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS:UniProtKB.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IDA:BHF-UCL.
DR GO; GO:0016241; P:regulation of macroautophagy; TAS:ParkinsonsUK-UCL.
DR GO; GO:0042391; P:regulation of membrane potential; IDA:BHF-UCL.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0050807; P:regulation of synapse organization; IBA:GO_Central.
DR GO; GO:0051592; P:response to calcium ion; TAS:BHF-UCL.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0043162; P:ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway; IMP:BHF-UCL.
DR GO; GO:0046755; P:viral budding; IMP:BHF-UCL.
DR CDD; cd00078; HECTc; 1.
DR CDD; cd00201; WW; 4.
DR Gene3D; 2.60.40.150; -; 1.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR000569; HECT_dom.
DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR InterPro; IPR001202; WW_dom.
DR InterPro; IPR036020; WW_dom_sf.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00397; WW; 4.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 4.
DR SUPFAM; SSF51045; SSF51045; 4.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 4.
DR PROSITE; PS50020; WW_DOMAIN_2; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell membrane; Cytoplasm;
KW Host-virus interaction; Membrane; Neurogenesis; Phosphoprotein;
KW Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1..1319
FT /note="E3 ubiquitin-protein ligase NEDD4"
FT /id="PRO_0000120319"
FT DOMAIN 610..643
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 767..800
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 840..873
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 892..925
FT /note="WW 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 984..1318
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT REGION 204..229
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 578..981
FT /note="Mediates interaction with TNIK"
FT /evidence="ECO:0000250"
FT REGION 755..780
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 796..834
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 1286
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT MOD_RES 576
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q62940"
FT MOD_RES 648
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P46935"
FT MOD_RES 670
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46935"
FT MOD_RES 742
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 747
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332"
FT VAR_SEQ 1..419
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:7788527,
FT ECO:0000303|Ref.4"
FT /id="VSP_038256"
FT VAR_SEQ 420..516
FT /note="SACLPSSQNVDCQININGELERPHSQMNKNHGILRRSISLGGAYPNISCLSS
FT LKHNCSKGGPSQLLIKFASGNEGKVDNLSRDSNRDCTNELSNSCK -> MATCAVEVFG
FT LLEDEENSRIVRVRVIAGIGLAKKDILGASDPYVRVTLYDPMNGVLTSVQTKTIKKSLN
FT PKWNEEILFRVHPQQHRLLFEVFDENRL (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:7788527,
FT ECO:0000303|Ref.4"
FT /id="VSP_038257"
FT VAR_SEQ 517..588
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_038258"
FT VAR_SEQ 589..604
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_038259"
FT VARIANT 33
FT /note="M -> V (in dbSNP:rs1912403)"
FT /id="VAR_061985"
FT VARIANT 627
FT /note="Y -> H (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036472"
FT VARIANT 679
FT /note="R -> Q (in dbSNP:rs2303580)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:16572171,
FT ECO:0000269|PubMed:7788527, ECO:0000269|Ref.4"
FT /id="VAR_047909"
FT VARIANT 698
FT /note="N -> S (in dbSNP:rs2303579)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:16572171,
FT ECO:0000269|PubMed:7788527, ECO:0000269|Ref.4"
FT /id="VAR_047910"
FT MUTAGEN 795
FT /note="W->A: Abolishes interaction with ARRDC3; when
FT associated with A-868 and A-920."
FT /evidence="ECO:0000269|PubMed:24379409"
FT MUTAGEN 868
FT /note="W->A: Abolishes interaction with ARRDC3; when
FT associated with A-795 and A-920."
FT /evidence="ECO:0000269|PubMed:24379409"
FT MUTAGEN 920
FT /note="W->A: Abolishes interaction with ARRDC3; when
FT associated with A-795 and A-868."
FT /evidence="ECO:0000269|PubMed:24379409"
FT CONFLICT 59
FT /note="A -> T (in Ref. 5; AL832063)"
FT /evidence="ECO:0000305"
FT CONFLICT 407
FT /note="N -> H (in Ref. 5; AL832063)"
FT /evidence="ECO:0000305"
FT CONFLICT 620
FT /note="Q -> R (in Ref. 4; AAT52215 and 8; AAI44285)"
FT /evidence="ECO:0000305"
FT CONFLICT 863
FT /note="T -> I (in Ref. 8; AAI36606/AAI44285)"
FT /evidence="ECO:0000305"
FT CONFLICT 1199
FT /note="L -> P (in Ref. 3; BAG65229)"
FT /evidence="ECO:0000305"
FT CONFLICT 1268
FT /note="S -> L (in Ref. 5; AL832063)"
FT /evidence="ECO:0000305"
FT STRAND 520..528
FT /evidence="ECO:0007829|PDB:3B7Y"
FT STRAND 546..549
FT /evidence="ECO:0007829|PDB:3B7Y"
FT STRAND 561..569
FT /evidence="ECO:0007829|PDB:3B7Y"
FT STRAND 841..843
FT /evidence="ECO:0007829|PDB:5AHT"
FT STRAND 846..850
FT /evidence="ECO:0007829|PDB:4N7F"
FT TURN 852..854
FT /evidence="ECO:0007829|PDB:2KQ0"
FT STRAND 856..860
FT /evidence="ECO:0007829|PDB:4N7F"
FT TURN 861..864
FT /evidence="ECO:0007829|PDB:4N7F"
FT STRAND 865..869
FT /evidence="ECO:0007829|PDB:4N7F"
FT TURN 871..873
FT /evidence="ECO:0007829|PDB:2KQ0"
FT HELIX 941..951
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 956..958
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 960..966
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 968..970
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 971..979
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 985..989
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 990..996
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1004..1019
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1022..1024
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1025..1031
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1037..1039
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1043..1046
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1050..1067
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1071..1073
FT /evidence="ECO:0007829|PDB:2XBB"
FT HELIX 1077..1083
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1091..1096
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1098..1109
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1113..1115
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1118..1125
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1128..1135
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1138..1140
FT /evidence="ECO:0007829|PDB:5C91"
FT TURN 1145..1147
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1148..1160
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1162..1164
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1165..1178
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1181..1184
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1189..1196
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1204..1209
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1212..1214
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1219..1221
FT /evidence="ECO:0007829|PDB:2XBF"
FT HELIX 1222..1233
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1236..1247
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1248..1250
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1257..1259
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1263..1266
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1270..1272
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1282..1284
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1285..1287
FT /evidence="ECO:0007829|PDB:5C91"
FT STRAND 1289..1291
FT /evidence="ECO:0007829|PDB:5C91"
FT HELIX 1298..1309
FT /evidence="ECO:0007829|PDB:5C91"
FT INIT_MET P46934-4:1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:22223895"
FT MOD_RES P46934-4:2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:22223895"
SQ SEQUENCE 1319 AA; 149114 MW; D56EBBC50A34F13B CRC64;
MAQSLRLHFA ARRSNTYPLS ETSGDDLDSH VHMCFKRPTR ISTSNVVQMK LTPRQTALAP
LIKENVQSQE RSSVPSSENV NKKSSCLQIS LQPTRYSGYL QSSNVLADSD DASFTCILKD
GIYSSAVVDN ELNAVNDGHL VSSPAICSGS LSNFSTSDNG SYSSNGSDFG SCASITSGGS
YTNSVISDSS SYTFPPSDDT FLGGNLPSDS TSNRSVPNRN TTPCEIFSRS TSTDPFVQDD
LEHGLEIMKL PVSRNTKIPL KRYSSLVIFP RSPSTTRPTS PTSLCTLLSK GSYQTSHQFI
ISPSEIAHNE DGTSAKGFLS TAVNGLRLSK TICTPGEVRD IRPLHRKGSL QKKIVLSNNT
PRQTVCEKSS EGYSCVSVHF TQRKAATLDC ETTNGDCKPE MSEIKLNSDS EYIKLMHRTS
ACLPSSQNVD CQININGELE RPHSQMNKNH GILRRSISLG GAYPNISCLS SLKHNCSKGG
PSQLLIKFAS GNEGKVDNLS RDSNRDCTNE LSNSCKTRDD FLGQVDVPLY PLPTENPRLE
RPYTFKDFVL HPRSHKSRVK GYLRLKMTYL PKTSGSEDDN AEQAEELEPG WVVLDQPDAA
CHLQQQQEPS PLPPGWEERQ DILGRTYYVN HESRRTQWKR PTPQDNLTDA ENGNIQLQAQ
RAFTTRRQIS EETESVDNRE SSENWEIIRE DEATMYSNQA FPSPPPSSNL DVPTHLAEEL
NARLTIFGNS AVSQPASSSN HSSRRGSLQA YTFEEQPTLP VLLPTSSGLP PGWEEKQDER
GRSYYVDHNS RTTTWTKPTV QATVETSQLT SSQSSAGPQS QASTSDSGQQ VTQPSEIEQG
FLPKGWEVRH APNGRPFFID HNTKTTTWED PRLKIPAHLR GKTSLDTSND LGPLPPGWEE
RTHTDGRIFY INHNIKRTQW EDPRLENVAI TGPAVPYSRD YKRKYEFFRR KLKKQNDIPN
KFEMKLRRAT VLEDSYRRIM GVKRADFLKA RLWIEFDGEK GLDYGGVARE WFFLISKEMF
NPYYGLFEYS ATDNYTLQIN PNSGLCNEDH LSYFKFIGRV AGMAVYHGKL LDGFFIRPFY
KMMLHKPITL HDMESVDSEY YNSLRWILEN DPTELDLRFI IDEELFGQTH QHELKNGGSE
IVVTNKNKKE YIYLVIQWRF VNRIQKQMAA FKEGFFELIP QDLIKIFDEN ELELLMCGLG
DVDVNDWREH TKYKNGYSAN HQVIQWFWKA VLMMDSEKRI RLLQFVTGTS RVPMNGFAEL
YGSNGPQSFT VEQWGTPEKL PRAHTCFNRL DLPPYESFEE LWDKLQMAIE NTQGFDGVD
