NED4L_MOUSE
ID NED4L_MOUSE Reviewed; 1004 AA.
AC Q8CFI0; Q8BRT9; Q8BS42; Q99PK2;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2005, sequence version 2.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=E3 ubiquitin-protein ligase NEDD4-like;
DE EC=2.3.2.26 {ECO:0000250|UniProtKB:P46934};
DE EC=2.3.2.36 {ECO:0000250|UniProtKB:P46934};
DE AltName: Full=HECT-type E3 ubiquitin transferase NED4L;
DE AltName: Full=NEDD4.2;
DE AltName: Full=Nedd4-2;
GN Name=Nedd4l; Synonyms=Kiaa0439, Nedd4b;
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] (ISOFORM 2), TISSUE SPECIFICITY, FUNCTION, AND
RP MUTAGENESIS OF CYS-971.
RC STRAIN=C57BL/6J;
RX PubMed=11149908; DOI=10.1096/fj.00-0191com;
RA Kamynina E., Debonneville C., Bens M., Vandewalle A., Staub O.;
RT "A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+
RT channel.";
RL FASEB J. 15:204-214(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), INTERACTION WITH SCNN1A;
RP SCNN1B AND SCNN1G, AND FUNCTION.
RC TISSUE=Brain;
RX PubMed=12424229; DOI=10.1096/fj.02-0497fje;
RA Fotia A.B., Dinudom A., Shearwin K.E., Koch J.-P., Korbmacher C.,
RA Cook D.I., Kumar S.;
RT "The role of individual Nedd4-2 (KIAA0439) WW domains in binding and
RT regulating epithelial sodium channels.";
RL FASEB J. 17:70-72(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=FVB/N; TISSUE=Kidney, and Mammary gland;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 44-1004 (ISOFORM 3).
RC STRAIN=C57BL/6J; TISSUE=Cerebellum;
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 FUNCTION, INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G, PHOSPHORYLATION AT
RP SER-371 AND SER-477, AND MUTAGENESIS OF SER-371 AND SER-477.
RX PubMed=11742982; DOI=10.1093/emboj/20.24.7052;
RA Debonneville C., Flores S.Y., Kamynina E., Plant P.J., Tauxe C.,
RA Thomas M.A., Muenster C., Chraiebi A., Pratt J.H., Horisberger J.-D.,
RA Pearce D., Loffing J., Staub O.;
RT "Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell
RT surface expression.";
RL EMBO J. 20:7052-7059(2001).
RN [6]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=11244092; DOI=10.1074/jbc.c000906200;
RA Harvey K.F., Dinudom A., Cook D.I., Kumar S.;
RT "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial
RT sodium channel.";
RL J. Biol. Chem. 276:8597-8601(2001).
RN [7]
RP INTERACTION WITH NDFIP2, AND SUBCELLULAR LOCATION.
RX PubMed=12050153; DOI=10.1074/jbc.m203018200;
RA Konstas A.-A., Shearwin-Whyatt L.M., Fotia A.B., Degger B., Riccardi D.,
RA Cook D.I., Korbmacher C., Kumar S.;
RT "Regulation of the epithelial sodium channel by N4WBP5A, a novel
RT Nedd4/Nedd4-2-interacting protein.";
RL J. Biol. Chem. 277:29406-29416(2002).
RN [8]
RP FUNCTION, AND INTERACTION WITH SCN1A; SCN2A; SCN3A; SCN5A; SCN8A; SCN9A;
RP SCN10A; SCNN1A; SCNN1B AND SCNN1G.
RX PubMed=15123669; DOI=10.1074/jbc.m402820200;
RA Fotia A.B., Ekberg J., Adams D.J., Cook D.I., Poronnik P., Kumar S.;
RT "Regulation of neuronal voltage-gated sodium channels by the ubiquitin-
RT protein ligases Nedd4 and Nedd4-2.";
RL J. Biol. Chem. 279:28930-28935(2004).
RN [9]
RP INTERACTION WITH UBE2E3.
RX PubMed=14993279; DOI=10.1128/mcb.24.6.2397-2409.2004;
RA Debonneville C., Staub O.;
RT "Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-
RT dependent regulation of the epithelial Na+ channel.";
RL Mol. Cell. Biol. 24:2397-2409(2004).
RN [10]
RP PHOSPHORYLATION AT SER-477.
RX PubMed=15958725; DOI=10.1681/asn.2004100828;
RA Flores S.Y., Loffing-Cueni D., Kamynina E., Daidie D., Gerbex C.,
RA Chabanel S., Dudler J., Loffing J., Staub O.;
RT "Aldosterone-induced serum and glucocorticoid-induced kinase 1 expression
RT is accompanied by nedd4-2 phosphorylation and increased na+ transport in
RT cortical collecting duct cells.";
RL J. Am. Soc. Nephrol. 16:2279-2287(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-508, 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 [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-478; SER-493; SER-508;
RP SER-512 AND SER-516, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Pancreas, Spleen,
RC 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 [13]
RP DEVELOPMENTAL STAGE.
RX PubMed=27694961; DOI=10.1038/ng.3676;
RG Deciphering Developmental Disorders study;
RA Broix L., Jagline H., Ivanova L.E., Schmucker S., Drouot N.,
RA Clayton-Smith J., Pagnamenta A.T., Metcalfe K.A., Isidor B., Louvier U.W.,
RA Poduri A., Taylor J.C., Tilly P., Poirier K., Saillour Y., Lebrun N.,
RA Stemmelen T., Rudolf G., Muraca G., Saintpierre B., Elmorjani A., Moise M.,
RA Weirauch N.B., Guerrini R., Boland A., Olaso R., Masson C., Tripathy R.,
RA Keays D., Beldjord C., Nguyen L., Godin J., Kini U., Nischke P.,
RA Deleuze J.F., Bahi-Buisson N., Sumara I., Hinckelmann M.V., Chelly J.;
RT "Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway
RT deregulation and cause periventricular nodular heterotopia.";
RL Nat. Genet. 48:1349-1358(2016).
RN [14]
RP STRUCTURE BY NMR OF 221-254; 414-447 AND 525-560.
RA Kowalski K., Merkel A.L., Booker G.W.;
RT "Solution structures of WW domains of NEDD4-2.";
RL Submitted (OCT-2005) to the PDB data bank.
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates the
CC polyubiquitination of lysine and cysteine residues on target proteins
CC and is thereby implicated in the regulation of various signaling
CC pathways including autophagy, innate immunity or DNA repair. Inhibits
CC TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and
CC proteasome-dependent degradation. Downregulates autophagy and cell
CC growth by ubiquitinating and reducing cellular ULK1 or ASCT2 levels.
CC Promotes ubiquitination and internalization of various plasma membrane
CC channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5,
CC SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2,
CC KCNQ3/Kv7.3 or CLC5 (PubMed:15123669). Promotes ubiquitination and
CC degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this
CC ubiquitination is enhanced in the presence of NDFIP1. Plays a role in
CC dendrite formation by melanocytes (By similarity). Involved in the
CC regulation of TOR signaling (By similarity). Ubiquitinates and
CC regulates protein levels of NTRK1 once this one is activated by NGF.
CC Plays a role in antiviral innate immunity by catalyzing 'Lys-29'-linked
CC cysteine ubiquitination of TRAF3, resulting in enhanced 'Lys-48' and
CC 'Lys-63'-linked ubiquitination of TRAF3 (By similarity).
CC {ECO:0000250|UniProtKB:Q96PU5, ECO:0000269|PubMed:11149908,
CC ECO:0000269|PubMed:11244092, ECO:0000269|PubMed:11742982,
CC ECO:0000269|PubMed:12424229, ECO:0000269|PubMed:15123669}.
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:Q96PU5};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine +
CC [acceptor protein]-L-cysteine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + [acceptor protein]-S-ubiquitinyl-L-cysteine.; EC=2.3.2.36;
CC Evidence={ECO:0000250|UniProtKB:Q96PU5};
CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC {ECO:0000250|UniProtKB:Q96PU5}.
CC -!- PATHWAY: Protein modification; protein ubiquitination. {ECO:0000305}.
CC -!- SUBUNIT: Interacts with UBE2E3 (PubMed:14993279). Interacts with
CC NDFIP1; this interaction activates the E3 ubiquitin-protein ligase (By
CC similarity). Interacts with NDFIP2; this interaction activates the E3
CC ubiquitin-protein ligase (PubMed:12050153). Interacts (via WW domains)
CC with SCNN1A (PubMed:11742982, PubMed:12424229, PubMed:15123669).
CC Interacts (via WW domains) with SCNN1B (PubMed:12424229,
CC PubMed:11742982). Interacts (via WW domains) with SCNN1G
CC (PubMed:12424229, PubMed:11742982, PubMed:15123669). Interacts (via WW
CC domains) with SCN1A (PubMed:15123669). Interacts (via WW domains) with
CC SCN2A (PubMed:15123669). Interacts (via WW domains) with SCN3A
CC (PubMed:15123669). Interacts (via WW domains) with SCN5A
CC (PubMed:15123669). Interacts (via WW domains) with SCN8A
CC (PubMed:15123669). Interacts (via WW domains) with SCN9A
CC (PubMed:15123669). Interacts (via WW domains) with SCN10A
CC (PubMed:15123669). Interacts (via WW domains) with CLCN5 (By
CC similarity). Interacts with SMAD2 (By similarity). Interacts with SMAD3
CC (By similarity). Interacts with SMAD6 (By similarity). Interacts with
CC SMAD7 (By similarity). The phosphorylated form interacts with 14-3-3
CC proteins (By similarity). Interacts with TNK2 (By similarity).
CC Interacts with WNK1 (By similarity). Interacts with SGK1 (By
CC similarity). Interacts (via C2 domain) with NPC2 (By similarity).
CC Interacts with ARRDC4 (By similarity). Interacts with KCNQ1; promotes
CC internalization of KCNQ1 (By similarity). Interacts (via domains WW1, 3
CC and 4) with USP36; the interaction inhibits ubiquitination of, at
CC least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (By similarity). Interacts with
CC PRRG4 (via cytoplasmic domain) (By similarity). Interacts with LDLRAD3;
CC the interaction is direct (By similarity). Interacts with UBE2D2 (By
CC similarity). {ECO:0000250|UniProtKB:Q96PU5,
CC ECO:0000269|PubMed:11742982, ECO:0000269|PubMed:12050153,
CC ECO:0000269|PubMed:12424229, ECO:0000269|PubMed:14993279,
CC ECO:0000269|PubMed:15123669}.
CC -!- INTERACTION:
CC Q8CFI0; Q99N57: Raf1; NbExp=2; IntAct=EBI-8046183, EBI-397757;
CC Q8CFI0; Q9Z2S7-3: Tsc22d3; NbExp=2; IntAct=EBI-8046183, EBI-15771036;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12050153}. Golgi
CC apparatus {ECO:0000250|UniProtKB:Q96PU5}. Endosome, multivesicular body
CC {ECO:0000250|UniProtKB:Q96PU5}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8CFI0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8CFI0-2; Sequence=VSP_015450;
CC Name=3;
CC IsoId=Q8CFI0-3; Sequence=VSP_015453;
CC -!- TISSUE SPECIFICITY: Highly expressed in liver and kidney. Also
CC expressed in heart, brain and lung. Isoform 1 is expressed in kidney,
CC lung and gut. Isoform 3 is ubiquitously expressed.
CC {ECO:0000269|PubMed:11149908, ECO:0000269|PubMed:11244092}.
CC -!- DEVELOPMENTAL STAGE: In the developing brain, it is homogenously
CC distributed in the cortical plate, ventricular zone and ganglionic
CC eminences at 15 dpc. A peak of expression in the cortex is observed at
CC 16.5 dpc. {ECO:0000269|PubMed:27694961}.
CC -!- PTM: Phosphorylated; which impairs interaction with SCNN. Interaction
CC with YWHAH inhibits dephosphorylation (By similarity). Aldosterone
CC induces Ser-477 phosphorylation by SGK1. {ECO:0000250,
CC ECO:0000269|PubMed:11742982, ECO:0000269|PubMed:15958725}.
CC -!- PTM: Auto-ubiquitinated. Deubiquitinated by USP36, no effect on NEDD4L
CC protein levels. Both proteins interact and regulate each other's
CC ubiquitination levels. {ECO:0000250|UniProtKB:Q96PU5}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC31307.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF277232; AAK00809.1; -; mRNA.
DR EMBL; BC039746; AAH39746.1; -; mRNA.
DR EMBL; BC071210; AAH71210.1; -; mRNA.
DR EMBL; AK042621; BAC31307.1; ALT_INIT; mRNA.
DR CCDS; CCDS29305.1; -. [Q8CFI0-2]
DR PDB; 1WR3; NMR; -; A=221-254.
DR PDB; 1WR4; NMR; -; A=414-447.
DR PDB; 1WR7; NMR; -; A=525-560.
DR PDBsum; 1WR3; -.
DR PDBsum; 1WR4; -.
DR PDBsum; 1WR7; -.
DR AlphaFoldDB; Q8CFI0; -.
DR BMRB; Q8CFI0; -.
DR SMR; Q8CFI0; -.
DR DIP; DIP-48843N; -.
DR IntAct; Q8CFI0; 10.
DR MINT; Q8CFI0; -.
DR STRING; 10090.ENSMUSP00000132838; -.
DR TCDB; 8.A.30.1.1; the nedd4-family interacting protein-2 (nedd4) family.
DR iPTMnet; Q8CFI0; -.
DR PhosphoSitePlus; Q8CFI0; -.
DR EPD; Q8CFI0; -.
DR jPOST; Q8CFI0; -.
DR MaxQB; Q8CFI0; -.
DR PaxDb; Q8CFI0; -.
DR PeptideAtlas; Q8CFI0; -.
DR PRIDE; Q8CFI0; -.
DR ProteomicsDB; 253057; -. [Q8CFI0-1]
DR ProteomicsDB; 253058; -. [Q8CFI0-2]
DR ProteomicsDB; 253059; -. [Q8CFI0-3]
DR Antibodypedia; 5421; 272 antibodies from 33 providers.
DR Ensembl; ENSMUST00000237410; ENSMUSP00000158044; ENSMUSG00000024589. [Q8CFI0-3]
DR UCSC; uc008fen.2; mouse. [Q8CFI0-3]
DR MGI; MGI:1933754; Nedd4l.
DR VEuPathDB; HostDB:ENSMUSG00000024589; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00940000156873; -.
DR InParanoid; Q8CFI0; -.
DR PhylomeDB; Q8CFI0; -.
DR Reactome; R-MMU-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
DR Reactome; R-MMU-2672351; Stimuli-sensing channels.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR ChiTaRS; Nedd4l; mouse.
DR EvolutionaryTrace; Q8CFI0; -.
DR PRO; PR:Q8CFI0; -.
DR Proteomes; UP000000589; Chromosome 18.
DR RNAct; Q8CFI0; protein.
DR Bgee; ENSMUSG00000024589; Expressed in caudate-putamen and 267 other tissues.
DR ExpressionAtlas; Q8CFI0; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0005771; C:multivesicular body; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0019870; F:potassium channel inhibitor activity; ISO:MGI.
DR GO; GO:0015459; F:potassium channel regulator activity; ISO:MGI.
DR GO; GO:0019871; F:sodium channel inhibitor activity; IDA:MGI.
DR GO; GO:0017080; F:sodium channel regulator activity; ISO:MGI.
DR GO; GO:0044325; F:transmembrane transporter binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0051649; P:establishment of localization in cell; IMP:MGI.
DR GO; GO:1901380; P:negative regulation of potassium ion transmembrane transport; ISO:MGI.
DR GO; GO:1901017; P:negative regulation of potassium ion transmembrane transporter activity; ISO:MGI.
DR GO; GO:2000009; P:negative regulation of protein localization to cell surface; ISO:MGI.
DR GO; GO:1902306; P:negative regulation of sodium ion transmembrane 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:0003085; P:negative regulation of systemic arterial blood pressure; IMP:MGI.
DR GO; GO:2001259; P:positive regulation of cation channel activity; IGI:MGI.
DR GO; GO:1903861; P:positive regulation of dendrite extension; ISO:MGI.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; IGI:MGI.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISO:MGI.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; ISO:MGI.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:2000810; P:regulation of bicellular tight junction assembly; IDA:MGI.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; IBA:GO_Central.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; ISO:MGI.
DR GO; GO:0003254; P:regulation of membrane depolarization; ISO:MGI.
DR GO; GO:0042391; P:regulation of membrane potential; ISO:MGI.
DR GO; GO:0060306; P:regulation of membrane repolarization; ISO:MGI.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; ISO:MGI.
DR GO; GO:0031647; P:regulation of protein stability; ISS:UniProtKB.
DR GO; GO:1902305; P:regulation of sodium ion transmembrane transport; ISS:UniProtKB.
DR GO; GO:0009651; P:response to salt stress; IMP:MGI.
DR GO; GO:0006814; P:sodium ion transport; IMP:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISO:MGI.
DR CDD; cd00078; HECTc; 1.
DR CDD; cd00201; WW; 4.
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; 4.
DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR PRINTS; PR00360; C2DOMAIN.
DR SMART; SM00239; C2; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 4.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF51045; SSF51045; 4.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50004; C2; 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; Alternative splicing; Cytoplasm; Differentiation; Endosome;
KW Golgi apparatus; Phosphoprotein; Reference proteome; Repeat; Transferase;
KW Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..1004
FT /note="E3 ubiquitin-protein ligase NEDD4-like"
FT /id="PRO_0000120324"
FT DOMAIN 30..154
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 221..254
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 414..447
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 526..559
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 577..610
FT /note="WW 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 669..1003
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT REGION 207..230
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 272..407
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 453..523
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 272..289
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 330..402
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 453..484
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 971
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT MOD_RES 341
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96PU5"
FT MOD_RES 347
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q96PU5"
FT MOD_RES 371
FT /note="Phosphoserine; by WNK1 and WNK4"
FT /evidence="ECO:0000269|PubMed:11742982"
FT MOD_RES 396
FT /note="Phosphothreonine; by SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q96PU5"
FT MOD_RES 475
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96PU5"
FT MOD_RES 477
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000269|PubMed:11742982,
FT ECO:0000269|PubMed:15958725"
FT MOD_RES 478
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 493
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 504
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96PU5"
FT MOD_RES 508
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 512
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 516
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT VAR_SEQ 1..149
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11149908,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_015450"
FT VAR_SEQ 385..404
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:12424229,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_015453"
FT MUTAGEN 371
FT /note="S->A: Weakly reduces phosphorylation by SGK1."
FT /evidence="ECO:0000269|PubMed:11742982"
FT MUTAGEN 477
FT /note="S->A: Strongly reduces phosphorylation by SGK1."
FT /evidence="ECO:0000269|PubMed:11742982"
FT MUTAGEN 971
FT /note="C->S: Abolishes activity."
FT /evidence="ECO:0000269|PubMed:11149908"
FT CONFLICT 179
FT /note="A -> G (in Ref. 1; AAK00809)"
FT /evidence="ECO:0000305"
FT CONFLICT 390
FT /note="R -> G (in Ref. 1; AAK00809)"
FT /evidence="ECO:0000305"
FT CONFLICT 403
FT /note="P -> S (in Ref. 1; AAK00809)"
FT /evidence="ECO:0000305"
FT CONFLICT 585
FT /note="E -> G (in Ref. 1; AAK00809)"
FT /evidence="ECO:0000305"
FT CONFLICT 832
FT /note="N -> T (in Ref. 1; AAK00809)"
FT /evidence="ECO:0000305"
FT CONFLICT 847
FT /note="N -> D (in Ref. 1; AAK00809)"
FT /evidence="ECO:0000305"
FT CONFLICT 949
FT /note="N -> K (in Ref. 4; BAC31307)"
FT /evidence="ECO:0000305"
FT STRAND 227..231
FT /evidence="ECO:0007829|PDB:1WR3"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:1WR3"
FT STRAND 237..241
FT /evidence="ECO:0007829|PDB:1WR3"
FT TURN 242..244
FT /evidence="ECO:0007829|PDB:1WR3"
FT STRAND 247..250
FT /evidence="ECO:0007829|PDB:1WR3"
FT STRAND 420..424
FT /evidence="ECO:0007829|PDB:1WR4"
FT STRAND 426..428
FT /evidence="ECO:0007829|PDB:1WR4"
FT STRAND 430..434
FT /evidence="ECO:0007829|PDB:1WR4"
FT TURN 435..438
FT /evidence="ECO:0007829|PDB:1WR4"
FT STRAND 439..443
FT /evidence="ECO:0007829|PDB:1WR4"
FT STRAND 532..536
FT /evidence="ECO:0007829|PDB:1WR7"
FT STRAND 542..546
FT /evidence="ECO:0007829|PDB:1WR7"
FT TURN 547..550
FT /evidence="ECO:0007829|PDB:1WR7"
FT STRAND 551..555
FT /evidence="ECO:0007829|PDB:1WR7"
FT HELIX 557..559
FT /evidence="ECO:0007829|PDB:1WR7"
SQ SEQUENCE 1004 AA; 115419 MW; 50CBB3436052AA60 CRC64;
MSLCEAPVHV GDKELKYFQI PQMLSQLSLL ASHHSRGLEF SGGQGESRIL RVKVVSGIDL
AKKDIFGASD PYVKLSLYVA DENRELALVQ TKTIKKTLNP KWNEEFYFRV NPSNHRLLFE
VFDENRLTRD DFLGQVDVPL SHLPTEDPTM ERPYTFKDFL LRPRSHKSRV KGFLRLKMAY
MPKNGGQDEE NSEQRDDMEH GWEVVDSNDS ASQHQEELPP PPLPPGWEEK VDNLGRTYYV
NHNNRSTQWH RPSLMDVSSE SDNNIRQINQ EAAHRRFRSR RHISEDLEPE ASEGGGEGPE
PWETISEEMN MAGDSLSLAL PPPPASPVSR TSPQELSEEV SRRLQITPDS NGEQFSSLIQ
REPSSRLRSC SVTDTVAEQA HLPPPSTPTR RARSSTVTGG EEPTPSVAYV HTTPGLPSGW
EERKDAKGRT YYVNHNNRTT TWTRPIMQLA EDGASGSATN SNNHLVEPQI RRPRSLSSPT
VTLSAPLEGA KDSPIRRAVK DTLSNPQSPQ PSPYNSPKPQ HKVTQSFLPP GWEMRIAPNG
RPFFIDHNTK TTTWEDPRLK FPVHMRSKAS LNPNDLGPLP PGWEERIHLD GRTFYIDHNS
KITQWEDPRL QNPAITGPAV PYSREFKQKY DYFRKKLKKP ADIPNRFEMK LHRNNIFEES
YRRIMSVKRP DVLKARLWIE FESEKGLDYG GVAREWFFLL SKEMFNPYYG LFEYSATDNY
TLQINPNSGL CNEDHLSYFT FIGRVAGLAV FHGKLLDGFF IRPFYKMMLG KQITLNDMES
VDSEYYNSLK WILENDPTEL DLMFCIDEEN FGQTYQVDLK PNGSEIMVTN ENKREYIDLV
IQWRFVNRVQ KQMNAFLEGF TELLPIDLIK IFDENELELL MCGLGDVDVN DWRQHSIYKN
GYCPNHPVIQ WFWKAVLLMD AEKRIRLLQF VTGTSRVPMN GFAELYGSNG PQLFTIEQWG
SPEKLPRAHT CFNRLDLPPY ETFEDLREKL LMAVENAQGF EGVD
