NEDD4_RAT
ID NEDD4_RAT Reviewed; 887 AA.
AC Q62940;
DT 03-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 172.
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;
GN Name=Nedd4; Synonyms=Nedd4a;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G.
RC TISSUE=Lung;
RX PubMed=8665844; DOI=10.1002/j.1460-2075.1996.tb00593.x;
RA Staub O., Dho S., Henry P., Correa J., Ishikawa T., McGlade J., Rotin D.;
RT "WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial
RT Na+ channel deleted in Liddle's syndrome.";
RL EMBO J. 15:2371-2380(1996).
RN [2]
RP FUNCTION, INTERACTION WITH RAP2A AND TNIK, SUBCELLULAR LOCATION,
RP DEVELOPMENTAL STAGE, AND TISSUE SPECIFICITY.
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 [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-212 AND SER-306, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [4]
RP STRUCTURE BY NMR OF 452-499 IN COMPLEX WITH SCNN1B, AND INTERACTION WITH
RP SCNN1A; SCNN1B AND SCNN1G.
RX PubMed=11323714; DOI=10.1038/87562;
RA Kanelis V., Rotin D., Forman-Kay J.D.;
RT "Solution structure of a Nedd4 WW domain-ENaC peptide complex.";
RL Nat. Struct. Biol. 8:407-412(2001).
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 Promotes ubiquitination of RAPGEF2. Involved in the pathway leading to
CC the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase
CC activity. Is involved in ubiquitination of ERBB4 intracellular domain
CC E4ICD. 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:20159449}.
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: Interacts with UBE2D2. Binds, in vitro, through the WW2 and
CC WW3 domains, to neural isoforms of ENAH that contain the PPSY motif.
CC Interacts with BEAN1, LITAF, RNF11, WBP1, WBP2, PMEPAI, NDFIP1, and
CC PRRG2 (By similarity). Interacts (via C2 domain) with GRB10 (via SH2
CC domain) (By similarity). Binds SCNN1A, SCNN1B and SCNN1G
CC (PubMed:8665844, PubMed:11323714). Interacts with ERBB4. Interacts with
CC NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein
CC ligase and may induce its recruitment to exosomes (By similarity).
CC Interacts with TNIK; the interaction is direct, allows the TNIK-
CC dependent recruitment of RAP2A and its ubiquitination by NEDD4
CC (PubMed:20159449). Interacts (via WW3 domain) with TNK2; EGF promotes
CC this interaction. Interacts (via WW3 domain) with FGFR1 (via C-
CC terminus). Interacts with OTUD7B (By similarity). Interacts with ISG15
CC (By similarity). Interacts (via WW domain) with RAPGEF2; this
CC interaction leads to ubiquitination and degradation via the proteasome
CC pathway. Interacts (via WW domains) with ARRDC3 (via PPXY motifs) (By
CC similarity). Interacts with LAPTM4B; may play a role in the lysosomal
CC sorting of LAPTM4B (By similarity). Interacts with ZBTB7B (By
CC similarity). Interacts with PRRG4 (via cytoplasmic domain) (By
CC similarity). Interacts directly with LDLRAD3; this interaction promotes
CC NEDD4 auto-ubiquitination (By similarity). Interacts with ADRB2 (By
CC similarity). {ECO:0000250|UniProtKB:P46934,
CC ECO:0000250|UniProtKB:P46935, ECO:0000269|PubMed:11323714,
CC ECO:0000269|PubMed:20159449, ECO:0000269|PubMed:8665844}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20159449}. Cell
CC membrane {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 (By similarity).
CC {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Expression is highest in
CC lung, kidney and brain. {ECO:0000269|PubMed:20159449}.
CC -!- DEVELOPMENTAL STAGE: Down-regulated after synapse formation.
CC {ECO:0000269|PubMed:20159449}.
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 (By similarity).
CC {ECO:0000250|UniProtKB:P46934, ECO:0000250|UniProtKB:P46935}.
CC -!- PTM: Auto-ubiquitinated. {ECO:0000250}.
CC -!- MISCELLANEOUS: A cysteine residue is required for ubiquitin-thioester
CC formation.
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DR EMBL; U50842; AAB48949.1; -; mRNA.
DR PIR; S70642; S70642.
DR RefSeq; NP_037118.1; NM_012986.1.
DR PDB; 1I5H; NMR; -; W=452-499.
DR PDB; 2N8S; NMR; -; A=245-281.
DR PDB; 2N8T; NMR; -; A=401-437.
DR PDB; 2N8U; NMR; -; A=401-437.
DR PDBsum; 1I5H; -.
DR PDBsum; 2N8S; -.
DR PDBsum; 2N8T; -.
DR PDBsum; 2N8U; -.
DR AlphaFoldDB; Q62940; -.
DR BMRB; Q62940; -.
DR SMR; Q62940; -.
DR BioGRID; 247522; 99.
DR IntAct; Q62940; 2.
DR MINT; Q62940; -.
DR STRING; 10116.ENSRNOP00000063797; -.
DR iPTMnet; Q62940; -.
DR PhosphoSitePlus; Q62940; -.
DR jPOST; Q62940; -.
DR PaxDb; Q62940; -.
DR PeptideAtlas; Q62940; -.
DR PRIDE; Q62940; -.
DR GeneID; 25489; -.
DR KEGG; rno:25489; -.
DR UCSC; RGD:3157; rat.
DR CTD; 4734; -.
DR RGD; 3157; Nedd4.
DR eggNOG; KOG0940; Eukaryota.
DR InParanoid; Q62940; -.
DR OrthoDB; 271539at2759; -.
DR PhylomeDB; Q62940; -.
DR Reactome; R-RNO-1169408; ISG15 antiviral mechanism.
DR Reactome; R-RNO-1253288; Downregulation of ERBB4 signaling.
DR Reactome; R-RNO-8948747; Regulation of PTEN localization.
DR Reactome; R-RNO-8948751; Regulation of PTEN stability and activity.
DR Reactome; R-RNO-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR EvolutionaryTrace; Q62940; -.
DR PRO; PR:Q62940; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005938; C:cell cortex; ISO:RGD.
DR GO; GO:0000785; C:chromatin; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0043197; C:dendritic spine; ISO:RGD.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0005794; C:Golgi apparatus; ISO:RGD.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0045121; C:membrane raft; IDA:RGD.
DR GO; GO:0005902; C:microvillus; IDA:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0099524; C:postsynaptic cytosol; ISO:RGD.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISO:RGD.
DR GO; GO:0031698; F:beta-2 adrenergic receptor binding; ISO:RGD.
DR GO; GO:0019899; F:enzyme binding; ISO:RGD.
DR GO; GO:0035255; F:ionotropic glutamate receptor binding; ISO:RGD.
DR GO; GO:0050815; F:phosphoserine residue binding; ISO:RGD.
DR GO; GO:0050816; F:phosphothreonine residue binding; ISO:RGD.
DR GO; GO:0070064; F:proline-rich region binding; ISO:RGD.
DR GO; GO:0008022; F:protein C-terminus binding; IDA:RGD.
DR GO; GO:0019904; F:protein domain specific binding; ISO:RGD.
DR GO; GO:0070063; F:RNA polymerase binding; ISO:RGD.
DR GO; GO:0019871; F:sodium channel inhibitor activity; ISO:RGD.
DR GO; GO:0043130; F:ubiquitin binding; ISO:RGD.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISO:RGD.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; ISO:RGD.
DR GO; GO:0048514; P:blood vessel morphogenesis; ISO:RGD.
DR GO; GO:0034644; P:cellular response to UV; ISO:RGD.
DR GO; GO:0003197; P:endocardial cushion development; ISO:RGD.
DR GO; GO:0044111; P:formation of structure involved in a symbiotic process; ISO:RGD.
DR GO; GO:0042921; P:glucocorticoid receptor signaling pathway; ISO:RGD.
DR GO; GO:0006955; P:immune response; IEP:RGD.
DR GO; GO:0007041; P:lysosomal transport; ISO:RGD.
DR GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; ISO:RGD.
DR GO; GO:0010766; P:negative regulation of sodium ion transport; ISO:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0010768; P:negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0031175; P:neuron projection development; ISO:RGD.
DR GO; GO:0003151; P:outflow tract morphogenesis; ISO:RGD.
DR GO; GO:0046824; P:positive regulation of nucleocytoplasmic transport; ISO:RGD.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISO:RGD.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; ISO:RGD.
DR GO; GO:0050847; P:progesterone receptor signaling pathway; ISO:RGD.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0006513; P:protein monoubiquitination; ISO:RGD.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0006622; P:protein targeting to lysosome; ISO:RGD.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0032801; P:receptor catabolic process; ISO:RGD.
DR GO; GO:0031623; P:receptor internalization; ISO:RGD.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; IDA:UniProtKB.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; ISO:RGD.
DR GO; GO:0042391; P:regulation of membrane potential; ISO:RGD.
DR GO; GO:0099149; P:regulation of postsynaptic neurotransmitter receptor internalization; IDA:SynGO.
DR GO; GO:1901016; P:regulation of potassium ion transmembrane transporter activity; ISO:RGD.
DR GO; GO:0099576; P:regulation of protein catabolic process at postsynapse, modulating synaptic transmission; IDA:SynGO.
DR GO; GO:0050807; P:regulation of synapse organization; ISO:RGD.
DR GO; GO:0014894; P:response to denervation involved in regulation of muscle adaptation; IEP:RGD.
DR GO; GO:0042110; P:T cell activation; ISO:RGD.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISO:RGD.
DR GO; GO:0043162; P:ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway; ISO:RGD.
DR GO; GO:0046755; P:viral budding; ISO:RGD.
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_0000120321"
FT DOMAIN 54..180
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 246..279
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 402..435
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 459..492
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 551..887
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT REGION 214..548
FT /note="Mediates interaction with TNIK"
FT /evidence="ECO:0000250"
FT REGION 297..319
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 362..384
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 396..440
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 422..436
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 854
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT MOD_RES 212
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 284
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P46935"
FT MOD_RES 306
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 377
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46934"
FT MOD_RES 382
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46934"
FT STRAND 252..256
FT /evidence="ECO:0007829|PDB:2N8S"
FT STRAND 262..266
FT /evidence="ECO:0007829|PDB:2N8S"
FT TURN 267..269
FT /evidence="ECO:0007829|PDB:2N8S"
FT STRAND 272..275
FT /evidence="ECO:0007829|PDB:2N8S"
FT STRAND 401..404
FT /evidence="ECO:0007829|PDB:2N8T"
FT STRAND 408..412
FT /evidence="ECO:0007829|PDB:2N8T"
FT STRAND 414..416
FT /evidence="ECO:0007829|PDB:2N8U"
FT STRAND 418..422
FT /evidence="ECO:0007829|PDB:2N8T"
FT TURN 423..426
FT /evidence="ECO:0007829|PDB:2N8T"
FT STRAND 427..429
FT /evidence="ECO:0007829|PDB:2N8U"
FT STRAND 454..456
FT /evidence="ECO:0007829|PDB:1I5H"
FT STRAND 465..469
FT /evidence="ECO:0007829|PDB:1I5H"
FT STRAND 475..479
FT /evidence="ECO:0007829|PDB:1I5H"
FT TURN 480..483
FT /evidence="ECO:0007829|PDB:1I5H"
FT STRAND 484..488
FT /evidence="ECO:0007829|PDB:1I5H"
FT TURN 490..492
FT /evidence="ECO:0007829|PDB:1I5H"
SQ SEQUENCE 887 AA; 102395 MW; D74B1097688CD9A1 CRC64;
MAADDTEAPV LSEDEVWEFC LDKNEEGGGS PGSDVTDTCE PPCGCWELNP SSLEEEHVLF
TAESIISSFN NDDTRVVRVK VIAGIGLAKK DILGASDPYV RVTLYDPMSG VLTSVQTKTI
KKSLNPKWNE EILFRVLPQQ HRILFEVFDE NRLTRDDFLG QVDVPLYPLP TENPRMERPY
TFKDFVLHPR SHKSRVKGYL RLKMTYLPKN GSDDENADQA EELEPGWVVL DQPDAATHLQ
HPPEPSPLPP GWEERQDVLG RTYYVNHESR TTQWKRPSPE DDLTDDENGD IQLQAHGAFT
TRRQISEDVD GPDNHESPEN WEIVREDENT IYSGQAVQSP PSGHPDVQVR LAEELDTRLT
MYGNPATSQP VTSSNHSSRG GSSQTCIFEE QPTLPVLLPT SSGLPPGWEE KQDDRGRSYY
VDHNSKTTTW SKPTMQDDPR SKIPAHLRGK TPVDSNDLGP LPPGWEERTH TDGRVFFINH
NIKKTQWEDP RMQNVAITGP AEPYSRDYKR KYEFFRRKLK KQTDIPNKFE MKLRRANILE
DSYRRIMGVK RADFLKARLW IEFDGEKGLD YGGVAREWFF LISKEMFNPY YGLFEYSATE
DNYTLQINPN SGLCNEDHLS YFKFIGRVAG MAVYHGKLLD GFFIRPFYKM MLQKLITLHD
MESVDSEYYS SLRWILENDP TELDLRFIID EELFGQTHQH ELKTGGSEVV VTNKNKKEYI
YLVIQWRFVN RIQKQMAAFK EGFFELIPQD LIKIFDENEL ELLMCGLGDV DVNDWREHTK
YKNGYSLNHQ VIHWFWKAVL MMDSEKRIRL LQFVTGTSRV PMNGFAELYG SNGPQSFTVE
QWGTPDKLPR AHTCFNRLDL PPYESFDELW DKLQMAIENT QGFDGVD
