NEDD4_MOUSE
ID NEDD4_MOUSE Reviewed; 887 AA.
AC P46935; O08758; Q3UZI2; Q8BGB3;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 20-JUN-2003, sequence version 3.
DT 03-AUG-2022, entry version 208.
DE RecName: Full=E3 ubiquitin-protein ligase NEDD4;
DE EC=2.3.2.26 {ECO:0000250|UniProtKB:P46934};
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, Nedd-4, Nedd4-1, Nedd4a;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Embryo;
RX PubMed=1378265; DOI=10.1016/0006-291x(92)91747-e;
RA Kumar S., Tomooka Y., Noda M.;
RT "Identification of a set of genes with developmentally down-regulated
RT expression in the mouse brain.";
RL Biochem. Biophys. Res. Commun. 185:1155-1161(1992).
RN [2]
RP SEQUENCE REVISION.
RA Kumar S.;
RL Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, AND INTERACTION WITH
RP UBE2D2.
RC STRAIN=C57BL/6 X CBA;
RX PubMed=9182527; DOI=10.1074/jbc.272.24.15085;
RA Hatakeyama S., Jensen J.P., Weissman A.M.;
RT "Subcellular localization and ubiquitin-conjugating enzyme (E2)
RT interactions of mammalian HECT family ubiquitin protein ligases.";
RL J. Biol. Chem. 272:15085-15092(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=12693553; DOI=10.1093/dnares/10.1.35;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Aizawa H., Yuasa S.,
RA Nakajima D., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: II.
RT The complete nucleotide sequences of 400 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:35-48(2003).
RN [6]
RP INTERACTION WITH ENAH.
RX PubMed=9407065; DOI=10.1074/jbc.272.52.32869;
RA Ermekova K.S., Zambrano N., Linn H., Minopoli G., Gertler F., Russo T.,
RA Sudol M.;
RT "The WW domain of neural protein FE65 interacts with proline-rich motifs in
RT Mena, the mammalian homolog of Drosophila enabled.";
RL J. Biol. Chem. 272:32869-32877(1997).
RN [7]
RP INTERACTION WITH BEAN1; LITAF; RNF11; WBP1; WBP2; PMEPAI; NDFIP1 AND PRRG2,
RP AND DOMAINS.
RC TISSUE=Embryo;
RX PubMed=11042109; DOI=10.1042/bj3510557;
RA Jolliffe C.N., Harvey K.F., Haines B.P., Parasivam G., Kumar S.;
RT "Identification of multiple proteins expressed in murine embryos as binding
RT partners for the WW domains of the ubiquitin-protein ligase Nedd4.";
RL Biochem. J. 351:557-565(2000).
RN [8]
RP INTERACTION WITH GRB10.
RX PubMed=12697834; DOI=10.1128/mcb.23.9.3363-3372.2003;
RA Vecchione A., Marchese A., Henry P., Rotin D., Morrione A.;
RT "The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and
RT stability of the insulin-like growth factor I receptor.";
RL Mol. Cell. Biol. 23:3363-3372(2003).
RN [9]
RP FUNCTION, INTERACTION WITH GRB10, AND MUTAGENESIS OF CYS-854.
RX PubMed=15060076; DOI=10.1074/jbc.m311802200;
RA Murdaca J., Treins C., Monthouel-Kartmann M.N., Pontier-Bres R., Kumar S.,
RA Van Obberghen E., Giorgetti-Peraldi S.;
RT "Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-
RT 2 degradation.";
RL J. Biol. Chem. 279:26754-26761(2004).
RN [10]
RP INTERACTION WITH MURINE LEUKEMIA VIRUS GAG POLYPROTEIN.
RX PubMed=15908698; DOI=10.1074/jbc.m413735200;
RA Segura-Morales C., Pescia C., Chatellard-Causse C., Sadoul R., Bertrand E.,
RA Basyuk E.;
RT "Tsg101 and Alix interact with murine leukemia virus Gag and cooperate with
RT Nedd4 ubiquitin ligases during budding.";
RL J. Biol. Chem. 280:27004-27012(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-309, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=16452087; DOI=10.1074/mcp.t500041-mcp200;
RA Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.;
RT "Comprehensive identification of phosphorylation sites in postsynaptic
RT density preparations.";
RL Mol. Cell. Proteomics 5:914-922(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-309, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [13]
RP FUNCTION, INTERACTION WITH GRB10, AND SUBCELLULAR LOCATION.
RX PubMed=18286479; DOI=10.1002/jcp.21405;
RA Monami G., Emiliozzi V., Morrione A.;
RT "Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor
RT receptor regulates receptor internalization.";
RL J. Cell. Physiol. 216:426-437(2008).
RN [14]
RP FUNCTION IN UBIQUITINATION OF ERBB4, AND INTERACTION WITH ERBB4.
RX PubMed=19193720; DOI=10.1096/fj.08-121947;
RA Zeng F., Xu J., Harris R.C.;
RT "Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK
RT II cells.";
RL FASEB J. 23:1935-1945(2009).
RN [15]
RP FUNCTION IN UBIQUITINATION OF ERBB4, INTERACTION WITH ERBB4, AND
RP SUBCELLULAR LOCATION.
RX PubMed=19047365; DOI=10.1128/mcb.00595-08;
RA Feng S.M., Muraoka-Cook R.S., Hunter D., Sandahl M.A., Caskey L.S.,
RA Miyazawa K., Atfi A., Earp H.S. III;
RT "The E3 ubiquitin ligase WWP1 selectively targets HER4 and its
RT proteolytically derived signaling isoforms for degradation.";
RL Mol. Cell. Biol. 29:892-906(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-287 AND SER-309, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=19131326; DOI=10.1074/mcp.m800451-mcp200;
RA Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.;
RT "Large scale localization of protein phosphorylation by use of electron
RT capture dissociation mass spectrometry.";
RL Mol. Cell. Proteomics 8:904-912(2009).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-287 AND SER-309, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [18]
RP FUNCTION, DISRUPTION PHENOTYPE, AND 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 [19]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 71-246 IN COMPLEX WITH GRB10, AND
RP INTERACTION WITH GRB10.
RX PubMed=20980250; DOI=10.1074/jbc.m110.143412;
RA Huang Q., Szebenyi D.M.;
RT "Structural basis for the interaction between the growth factor-binding
RT protein GRB10 and the E3 ubiquitin ligase NEDD4.";
RL J. Biol. Chem. 285:42130-42139(2010).
RN [20]
RP INTERACTION WITH ZBTB7B.
RX PubMed=28784777; DOI=10.1073/pnas.1703494114;
RA Li S., Mi L., Yu L., Yu Q., Liu T., Wang G.X., Zhao X.Y., Wu J., Lin J.D.;
RT "Zbtb7b engages the long noncoding RNA Blnc1 to drive brown and beige fat
RT development and thermogenesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:E7111-E7120(2017).
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 (By similarity).
CC Monoubiquitinates IGF1R at multiple sites, thus leading to receptor
CC internalization and degradation in lysosomes. Ubiquitinates FGFR1,
CC leading to receptor internalization and degradation in lysosomes.
CC Involved in ubiquitination of ERBB4 intracellular domain E4ICD1
CC (PubMed:19193720). Predominantly involved in ubiquitination of membrane
CC bound forms of ERBB4 rather than processed precursors and intermediate
CC membrane-anchored 80 kDa fragments (m80HER4), with a lesser role in
CC ubiquitination of ERBB4 intracellular domain E4ICD1 (PubMed:19047365).
CC Promotes ubiquitination of RAPGEF2. Involved in the pathway leading to
CC the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase
CC activity. Part of a signaling complex composed of NEDD4, RAP2A and TNIK
CC which regulates neuronal dendrite extension and arborization during
CC development. Ubiquitinates TNK2 and regulates EGF-induced degradation
CC of EGFR and TNF2 (By similarity). Involved in the ubiquitination of
CC ebola virus VP40 protein and this ubiquitination plays a role in
CC facilitating viral budding. Ubiquitinates BRAT1 and this ubiquitination
CC is enhanced in the presence of NDFIP1 (By similarity).
CC {ECO:0000250|UniProtKB:P46934, ECO:0000269|PubMed:19047365,
CC ECO:0000269|PubMed:19193720}.
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:0000250|UniProtKB:P46934};
CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC {ECO:0000250}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Binds SCNN1A, SCNN1B and SCNN1G. Interacts with NDFIP1 and
CC NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and
CC may induce its recruitment to exosomes. Interacts with UBE2D2
CC (PubMed:9182527). Binds, in vitro, through the WW2 and WW3 domains, to
CC neural isoforms of ENAH that contain the PPSY motif (PubMed:9407065).
CC Interacts with BEAN1, LITAF, RNF11, WBP1, WBP2, PMEPAI and PRRG2
CC (PubMed:11042109). Interacts with murine leukemia virus Gag polyprotein
CC (via PPXY motif) (PubMed:15908698). Interacts (via C2 domain) with
CC GRB10 (via SH2 domain) (PubMed:12697834, PubMed:15060076,
CC PubMed:18286479, PubMed:20980250). Interacts with ERBB4
CC (PubMed:19193720, PubMed:19047365). Interacts with TNIK; the
CC interaction is direct, allows the TNIK-dependent recruitment of RAP2A
CC and its ubiquitination by NEDD4 (PubMed:20159449). Interacts (via WW3
CC domain) with TNK2; EGF promotes this interaction. Interacts (via WW3
CC domain) with FGFR1 (via C-terminus). Interacts with OTUD7B (By
CC similarity). Interacts with ISG15 (By similarity). Interacts (via WW
CC domain) with RAPGEF2; this interaction leads to ubiquitination and
CC degradation via the proteasome pathway. Interacts (via WW domains) with
CC ARRDC3 (via PPXY motifs) (By similarity). Interacts with LAPTM4B; may
CC play a role in the lysosomal sorting of LAPTM4B (By similarity).
CC Interacts with ZBTB7B (PubMed:28784777). Interacts with PRRG4 (via
CC cytoplasmic domain) (By similarity). Interacts directly with LDLRAD3;
CC this interaction promotes NEDD4 auto-ubiquitination (By similarity).
CC Interacts with ADRB2 (By similarity). {ECO:0000250|UniProtKB:P46934,
CC ECO:0000269|PubMed:11042109, ECO:0000269|PubMed:12697834,
CC ECO:0000269|PubMed:15060076, ECO:0000269|PubMed:15908698,
CC ECO:0000269|PubMed:18286479, ECO:0000269|PubMed:19047365,
CC ECO:0000269|PubMed:19193720, ECO:0000269|PubMed:20159449,
CC ECO:0000269|PubMed:20980250, ECO:0000269|PubMed:28784777,
CC ECO:0000269|PubMed:9182527, ECO:0000269|PubMed:9407065}.
CC -!- INTERACTION:
CC P46935; Q9EQG5: Bean1; NbExp=3; IntAct=EBI-773516, EBI-6304006;
CC P46935; Q60760: Grb10; NbExp=6; IntAct=EBI-773516, EBI-861810;
CC P46935; Q9JLJ0: Litaf; NbExp=5; IntAct=EBI-773516, EBI-643664;
CC P46935; Q8R0W6: Ndfip1; NbExp=5; IntAct=EBI-773516, EBI-6304119;
CC P46935; Q9D7R2: Pmepa1; NbExp=5; IntAct=EBI-773516, EBI-6304097;
CC P46935; Q8R182: Prrg2; NbExp=5; IntAct=EBI-773516, EBI-6304055;
CC P46935; Q9QYK7: Rnf11; NbExp=4; IntAct=EBI-773516, EBI-4405826;
CC P46935; P97764: Wbp1; NbExp=3; IntAct=EBI-773516, EBI-6304160;
CC P46935; P97765: Wbp2; NbExp=5; IntAct=EBI-773516, EBI-6304181;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane; Peripheral membrane
CC protein. Note=Recruited to the plasma membrane by GRB10. Once complexed
CC with GRB10 and IGF1R, follows IGF1R internalization, remaining
CC associated with early endosomes. Uncouples from IGF1R-containing
CC endosomes before the sorting of the receptor to the lysosomal
CC compartment (By similarity). May be recruited to exosomes by NDFIP1.
CC {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Brain.
CC -!- DOMAIN: The WW domains mediate interaction with PPxY motif-containing
CC proteins (By similarity). The WW domains mediate interaction with
CC LITAF, RNF11, WBP1, WBP2, PMEPAI, NDFIP1 and PRRG2 (PubMed:11042109).
CC {ECO:0000250|UniProtKB:P46934, ECO:0000269|PubMed:11042109}.
CC -!- PTM: Auto-ubiquitinated. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Lethal during late gestation. Embryos show a
CC retarded development and defects in vasculogenesis and angiogenesis.
CC {ECO:0000269|PubMed:20159449}.
CC -!- MISCELLANEOUS: A cysteine residue is required for ubiquitin-thioester
CC formation.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB63360.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; D85414; BAA12803.1; -; mRNA.
DR EMBL; U96635; AAB63360.1; ALT_FRAME; mRNA.
DR EMBL; AK088620; BAC40458.1; -; mRNA.
DR EMBL; AK088767; BAC40558.1; -; mRNA.
DR EMBL; AK122203; BAC65485.1; -; mRNA.
DR EMBL; AK133838; BAE21875.1; -; mRNA.
DR CCDS; CCDS72275.1; -.
DR RefSeq; NP_035020.2; NM_010890.3.
DR PDB; 3M7F; X-ray; 2.00 A; B=71-246.
DR PDBsum; 3M7F; -.
DR AlphaFoldDB; P46935; -.
DR SMR; P46935; -.
DR BioGRID; 201723; 83.
DR DIP; DIP-32323N; -.
DR ELM; P46935; -.
DR IntAct; P46935; 21.
DR MINT; P46935; -.
DR STRING; 10090.ENSMUSP00000034740; -.
DR iPTMnet; P46935; -.
DR PhosphoSitePlus; P46935; -.
DR SwissPalm; P46935; -.
DR EPD; P46935; -.
DR jPOST; P46935; -.
DR MaxQB; P46935; -.
DR PaxDb; P46935; -.
DR PRIDE; P46935; -.
DR ProteomicsDB; 252877; -.
DR Antibodypedia; 25114; 306 antibodies from 39 providers.
DR DNASU; 17999; -.
DR Ensembl; ENSMUST00000034740; ENSMUSP00000034740; ENSMUSG00000032216.
DR GeneID; 17999; -.
DR KEGG; mmu:17999; -.
DR UCSC; uc009qqe.1; mouse.
DR CTD; 4734; -.
DR MGI; MGI:97297; Nedd4.
DR VEuPathDB; HostDB:ENSMUSG00000032216; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00940000158905; -.
DR HOGENOM; CLU_002173_0_3_1; -.
DR InParanoid; P46935; -.
DR OMA; PPYQDYE; -.
DR OrthoDB; 271539at2759; -.
DR PhylomeDB; P46935; -.
DR TreeFam; TF323658; -.
DR Reactome; R-MMU-1169408; ISG15 antiviral mechanism.
DR Reactome; R-MMU-1253288; Downregulation of ERBB4 signaling.
DR Reactome; R-MMU-8948747; Regulation of PTEN localization.
DR Reactome; R-MMU-8948751; Regulation of PTEN stability and activity.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 17999; 0 hits in 66 CRISPR screens.
DR ChiTaRS; Nedd4; mouse.
DR PRO; PR:P46935; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; P46935; protein.
DR Bgee; ENSMUSG00000032216; Expressed in metanephric loop of Henle and 264 other tissues.
DR ExpressionAtlas; P46935; baseline and differential.
DR Genevisible; P46935; MM.
DR GO; GO:0005938; C:cell cortex; ISO:MGI.
DR GO; GO:0000785; C:chromatin; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0043197; C:dendritic spine; IDA:SynGO.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0005902; C:microvillus; ISO:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0099524; C:postsynaptic cytosol; IDA:SynGO.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0000151; C:ubiquitin ligase complex; IPI:MGI.
DR GO; GO:0031698; F:beta-2 adrenergic receptor binding; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0035255; F:ionotropic glutamate receptor binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0050815; F:phosphoserine residue binding; IDA:BHF-UCL.
DR GO; GO:0050816; F:phosphothreonine residue binding; IDA:BHF-UCL.
DR GO; GO:0070064; F:proline-rich region binding; IPI:MGI.
DR GO; GO:0008022; F:protein C-terminus binding; ISO:MGI.
DR GO; GO:0019904; F:protein domain specific binding; ISO:MGI.
DR GO; GO:0070063; F:RNA polymerase binding; ISO:MGI.
DR GO; GO:0019871; F:sodium channel inhibitor activity; IDA:MGI.
DR GO; GO:0043130; F:ubiquitin binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISO:MGI.
DR GO; GO:0002250; P:adaptive immune response; IMP:MGI.
DR GO; GO:0048514; P:blood vessel morphogenesis; IMP:MGI.
DR GO; GO:0034644; P:cellular response to UV; ISO:MGI.
DR GO; GO:0003197; P:endocardial cushion development; IMP:MGI.
DR GO; GO:0051649; P:establishment of localization in cell; IDA:MGI.
DR GO; GO:0044111; P:formation of structure involved in a symbiotic process; ISO:MGI.
DR GO; GO:0042921; P:glucocorticoid receptor signaling pathway; ISO:MGI.
DR GO; GO:0007041; P:lysosomal transport; ISO:MGI.
DR GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; ISO:MGI.
DR GO; GO:0010766; P:negative regulation of sodium ion transport; IDA:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:MGI.
DR GO; GO:0010768; P:negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage; ISO:MGI.
DR GO; GO:0030948; P:negative regulation of vascular endothelial growth factor receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007528; P:neuromuscular junction development; IMP:MGI.
DR GO; GO:0031175; P:neuron projection development; IBA:GO_Central.
DR GO; GO:0003151; P:outflow tract morphogenesis; IMP:MGI.
DR GO; GO:0046824; P:positive regulation of nucleocytoplasmic transport; ISO:MGI.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISO:MGI.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:MGI.
DR GO; GO:0050847; P:progesterone receptor signaling pathway; ISO:MGI.
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:0006513; P:protein monoubiquitination; IDA:MGI.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0006622; P:protein targeting to lysosome; ISO:MGI.
DR GO; GO:0016567; P:protein ubiquitination; IDA:MGI.
DR GO; GO:0032801; P:receptor catabolic process; ISO:MGI.
DR GO; GO:0031623; P:receptor internalization; ISO:MGI.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; IMP:UniProtKB.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; ISO:MGI.
DR GO; GO:0042391; P:regulation of membrane potential; ISO:MGI.
DR GO; GO:0099149; P:regulation of postsynaptic neurotransmitter receptor internalization; ISO:MGI.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; ISO:MGI.
DR GO; GO:0099576; P:regulation of protein catabolic process at postsynapse, modulating synaptic transmission; ISO:MGI.
DR GO; GO:0050807; P:regulation of synapse organization; IMP:MGI.
DR GO; GO:0006814; P:sodium ion transport; IDA:MGI.
DR GO; GO:0042110; P:T cell activation; IMP:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:MGI.
DR GO; GO:0043162; P:ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway; ISO:MGI.
DR GO; GO:0046755; P:viral budding; ISO:MGI.
DR CDD; cd00078; HECTc; 1.
DR CDD; cd00201; WW; 3.
DR Gene3D; 2.60.40.150; -; 1.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR024928; E3_ub_ligase_SMURF1.
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; PF00168; C2; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00397; WW; 3.
DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 3.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF51045; SSF51045; 3.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 3.
DR PROSITE; PS50020; WW_DOMAIN_2; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Cytoplasm; Membrane; Neurogenesis;
KW Phosphoprotein; Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1..887
FT /note="E3 ubiquitin-protein ligase NEDD4"
FT /id="PRO_0000120320"
FT DOMAIN 58..183
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 249..282
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 405..438
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 460..493
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 552..887
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT REGION 217..549
FT /note="Mediates interaction with TNIK"
FT /evidence="ECO:0000269|PubMed:20159449"
FT REGION 236..257
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 271..290
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 302..322
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 271..285
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 306..322
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 854
FT /note="Glycyl thioester intermediate"
FT MOD_RES 215
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q62940"
FT MOD_RES 287
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19131326,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 309
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16452087,
FT ECO:0007744|PubMed:17242355, ECO:0007744|PubMed:19131326,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 380
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46934"
FT MOD_RES 385
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46934"
FT MUTAGEN 854
FT /note="C->S: Loss of ubiquitin-ligase activity. No effect
FT on VEGFR-2/KDFR degradation."
FT /evidence="ECO:0000269|PubMed:15060076"
FT STRAND 78..89
FT /evidence="ECO:0007829|PDB:3M7F"
FT STRAND 101..109
FT /evidence="ECO:0007829|PDB:3M7F"
FT TURN 110..112
FT /evidence="ECO:0007829|PDB:3M7F"
FT STRAND 113..119
FT /evidence="ECO:0007829|PDB:3M7F"
FT STRAND 130..139
FT /evidence="ECO:0007829|PDB:3M7F"
FT TURN 141..143
FT /evidence="ECO:0007829|PDB:3M7F"
FT STRAND 145..152
FT /evidence="ECO:0007829|PDB:3M7F"
FT STRAND 160..169
FT /evidence="ECO:0007829|PDB:3M7F"
FT STRAND 186..189
FT /evidence="ECO:0007829|PDB:3M7F"
FT STRAND 201..209
FT /evidence="ECO:0007829|PDB:3M7F"
SQ SEQUENCE 887 AA; 102706 MW; AE7DD3ED63986C50 CRC64;
MSSDMAADES EAPVLSEDEV WEFCLDKTED GGGSPGSDVT DTCEPPCGCW ELNPNSLEEE
HVLFTADPYL ELHNDDTRVV RVKVIAGIGL AKKDILGASD PYVRVTLYDP MSGILTSVQT
KTIKKSLNPK WNEEILFRVL PQRHRILFEV FDENRLTRDD FLGQVDVPLY PLPTENPRME
RPYTFKDFVL HPRSHKSRVK GYLRLKMTYL PKNGSEDENA DQAEELEPGW VVLDQPDAAT
HLPHPPEPSP LPPGWEERQD VLGRTYYVNH ESRRTQWKRP SPDDDLTDED NDDMQLQAQR
AFTTRRQISE DVDGPDNRES PENWEIVRED ENTEYSGQAV QSPPSGHIDV QTHLAEEFNT
RLAVCGNPAT SQPVTSSNHS SRGGSLQTCI FEEQPTLPVL LPTSSGLPPG WEEKQDDRGR
SYYVDHNSKT TTWSKPTMQD DPRSKIPAHL RGKTDSNDLG PLPPGWEERT HTDGRVFFIN
HNIKKTQWED PRLQNVAITG PAVPYSRDYK RKYEFFRRKL KKQTDIPNKF EMKLRRANIL
EDSYRRIMGV KRADLLKARL WIEFDGEKGL DYGGVAREWF FLISKEMFNP YYGLFEYSAT
DNYTLQINPN SGLCNEDHLS YFKFIGRVAG MAVYHGKLLD GFFIRPFYKM MLQKLITLHD
MESVDSEYYS SLRWILENDP TELDLRFIID EELFGQTHQH ELKTGGSEIV VTNKNKKEYI
YLVIQWRFVN RIQKQMAAFK EGFFELIPQD LIKIFDENEL ELLMCGLGDV DVNDWREHTK
YKNGYSMNHQ VIHWFWKAVW MMDSEKRIRL LQFVTGTSRV PMNGFAELYG SNGPQSFTVE
QWGTPDKLPR AHTCFNRLDL PPYESFDELW DKLQMAIENT QGFDGVD
