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Protein

E3 ubiquitin-protein ligase NEDD4

Gene

Nedd4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Specifically ubiquitinates 'Lys-63' in target proteins (By similarity). Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Involved in ubiquitination of ERBB4 intracellular domain E4ICD1 (PubMed:19193720). Predominantly involved in ubiquitination of membrane bound forms of ERBB4 rather than processed precursors and intermediate membrane-anchored 80 kDa fragments (m80HER4), with a lesser role in ubiquitination of ERBB4 intracellular domain E4ICD1 (PubMed:19047365). Promotes ubiquitination of RAPGEF2. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2 (By similarity). Involved in the ubiquitination of ebola virus VP40 protein and this ubiquitination plays a role in facilitating viral budding. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (By similarity).By similarity2 Publications

Enzyme regulationi

Activated by NDFIP1- and NDFIP2-binding.By similarity

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei854 – 8541Glycyl thioester intermediate

GO - Molecular functioni

  • ionotropic glutamate receptor binding Source: ParkinsonsUK-UCL
  • ligase activity Source: UniProtKB-KW
  • phosphoserine binding Source: BHF-UCL
  • phosphothreonine binding Source: BHF-UCL
  • proline-rich region binding Source: MGI
  • sodium channel inhibitor activity Source: MGI
  • ubiquitin protein ligase activity Source: MGI

GO - Biological processi

  • adaptive immune response Source: MGI
  • blood vessel morphogenesis Source: MGI
  • development involved in symbiotic interaction Source: Ensembl
  • endocardial cushion development Source: MGI
  • glucocorticoid receptor signaling pathway Source: Ensembl
  • negative regulation of sodium ion transmembrane transporter activity Source: Ensembl
  • negative regulation of sodium ion transport Source: MGI
  • negative regulation of transcription from RNA polymerase II promoter Source: MGI
  • negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage Source: Ensembl
  • negative regulation of vascular endothelial growth factor receptor signaling pathway Source: UniProtKB
  • neuromuscular junction development Source: MGI
  • neuron projection development Source: Ensembl
  • outflow tract morphogenesis Source: MGI
  • positive regulation of nucleocytoplasmic transport Source: Ensembl
  • positive regulation of phosphatidylinositol 3-kinase signaling Source: Ensembl
  • positive regulation of protein catabolic process Source: MGI
  • progesterone receptor signaling pathway Source: Ensembl
  • protein K63-linked ubiquitination Source: UniProtKB
  • protein monoubiquitination Source: MGI
  • protein targeting to lysosome Source: Ensembl
  • protein ubiquitination Source: MGI
  • protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: MGI
  • receptor catabolic process Source: Ensembl
  • receptor internalization Source: Ensembl
  • regulation of dendrite morphogenesis Source: UniProtKB
  • regulation of membrane potential Source: Ensembl
  • regulation of potassium ion transmembrane transporter activity Source: Ensembl
  • regulation of synapse organization Source: MGI
  • response to denervation involved in regulation of muscle adaptation Source: Ensembl
  • T cell activation Source: MGI
  • transmission of virus Source: Ensembl
  • ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Neurogenesis, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-MMU-1169408. ISG15 antiviral mechanism.
R-MMU-1253288. Downregulation of ERBB4 signaling.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase NEDD4 (EC:6.3.2.-)
Alternative name(s):
Neural precursor cell expressed developmentally down-regulated protein 4
Short name:
NEDD-4
Gene namesi
Name:Nedd4
Synonyms:Kiaa0093, Nedd-4, Nedd4-1, Nedd4a
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:97297. Nedd4.

Subcellular locationi

  • Cytoplasm
  • Cell membrane; Peripheral membrane protein

  • Note: Recruited to the plasma membrane by GRB10. Once complexed with GRB10 and IGF1R, follows IGF1R internalization, remaining associated with early endosomes. Uncouples from IGF1R-containing endosomes before the sorting of the receptor to the lysosomal compartment (By similarity). May be recruited to exosomes by NDFIP1.By similarity

GO - Cellular componenti

  • cell cortex Source: Ensembl
  • chromatin Source: Ensembl
  • cytoplasm Source: MGI
  • cytosol Source: MGI
  • extracellular exosome Source: Ensembl
  • Golgi apparatus Source: Ensembl
  • membrane Source: MGI
  • membrane raft Source: Ensembl
  • microvillus Source: Ensembl
  • nucleus Source: GO_Central
  • perinuclear region of cytoplasm Source: Ensembl
  • plasma membrane Source: UniProtKB-SubCell
  • ubiquitin ligase complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Disruption phenotypei

Lethal during late gestation. Embryos show a retarded development and defects in vasculogenesis and angiogenesis.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi854 – 8541C → S: Loss of ubiquitin-ligase activity. No effect on VEGFR-2/KDFR degradation. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 887887E3 ubiquitin-protein ligase NEDD4PRO_0000120320Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei215 – 2151PhosphoserineBy similarity
Modified residuei287 – 2871PhosphothreonineCombined sources
Modified residuei309 – 3091Phosphoserine; by hostCombined sources
Modified residuei380 – 3801PhosphoserineBy similarity
Modified residuei385 – 3851Phosphoserine; by hostBy similarity

Post-translational modificationi

Auto-ubiquitinated.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP46935.
MaxQBiP46935.
PaxDbiP46935.
PRIDEiP46935.

PTM databases

iPTMnetiP46935.
PhosphoSiteiP46935.
SwissPalmiP46935.

Expressioni

Tissue specificityi

Brain.

Gene expression databases

BgeeiENSMUSG00000032216.
ExpressionAtlasiP46935. baseline and differential.
GenevisibleiP46935. MM.

Interactioni

Subunit structurei

Binds SCNN1A, SCNN1B and SCNN1G. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes. Interacts with UBE2D2 (PubMed:9182527). Binds, in vitro, through the WW2 and WW3 domains, to neural isoforms of ENAH that contain the PPSY motif (PubMed:9407065). Interacts with BEAN1, LITAF, RNF11, WBP1, WBP2, TMEPAI and PRRG2 (PubMed:11042109). Interacts with murine leukemia virus Gag polyprotein (via PPXY motif) (PubMed:15908698). Interacts (via C2 domain) with GRB10 (via SH2 domain) (PubMed:12697834, PubMed:15060076, PubMed:18286479, PubMed:20980250). Interacts with ERBB4 (PubMed:19193720, PubMed:19047365). Interacts with TNIK; the interaction is direct, allows the TNIK-dependent recruitment of RAP2A and its ubiquitination by NEDD4 (PubMed:20159449). Interacts (via WW3 domain) with TNK2; EGF promotes this interaction. Interacts (via WW3 domain) with FGFR1 (via C-terminus). Interacts with OTUD7B (By similarity). Interacts with ISG15 (By similarity). Interacts (via WW domain) with RAPGEF2; this interaction leads to ubiquitination and degradation via the proteasome pathway. Interacts (via WW domains) with ARRDC3 (via PPXY motifs) (By similarity).By similarity11 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Bean1Q9EQG53EBI-773516,EBI-6304006
Grb10Q607606EBI-773516,EBI-861810
LitafQ9JLJ05EBI-773516,EBI-643664
Ndfip1Q8R0W65EBI-773516,EBI-6304119
Pmepa1Q9D7R25EBI-773516,EBI-6304097
Prrg2Q8R1825EBI-773516,EBI-6304055
Rnf11Q9QYK74EBI-773516,EBI-4405826
Wbp1P977643EBI-773516,EBI-6304160
Wbp2P977655EBI-773516,EBI-6304181

GO - Molecular functioni

  • ionotropic glutamate receptor binding Source: ParkinsonsUK-UCL
  • phosphoserine binding Source: BHF-UCL
  • phosphothreonine binding Source: BHF-UCL
  • proline-rich region binding Source: MGI

Protein-protein interaction databases

BioGridi201723. 50 interactions.
DIPiDIP-32323N.
IntActiP46935. 16 interactions.
MINTiMINT-90132.
STRINGi10090.ENSMUSP00000034740.

Structurei

Secondary structure

1
887
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi78 – 8912Combined sources
Beta strandi101 – 1099Combined sources
Turni110 – 1123Combined sources
Beta strandi113 – 1197Combined sources
Beta strandi130 – 13910Combined sources
Turni141 – 1433Combined sources
Beta strandi145 – 1528Combined sources
Beta strandi160 – 16910Combined sources
Beta strandi186 – 1894Combined sources
Beta strandi201 – 2099Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3M7FX-ray2.00B71-246[»]
ProteinModelPortaliP46935.
SMRiP46935. Positions 71-246, 250-281, 406-883.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini65 – 166102C2PROSITE-ProRule annotationAdd
BLAST
Domaini249 – 28234WW 1PROSITE-ProRule annotationAdd
BLAST
Domaini405 – 43834WW 2PROSITE-ProRule annotationAdd
BLAST
Domaini460 – 49334WW 3PROSITE-ProRule annotationAdd
BLAST
Domaini552 – 887336HECTPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni217 – 549333Mediates interaction with TNIKAdd
BLAST

Domaini

The WW domains mediate interaction with LITAF, RNF11, WBP1, WBP2, TMEPAI, NDFIP1 and PRRG2.1 Publication

Sequence similaritiesi

Contains 1 C2 domain.PROSITE-ProRule annotation
Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.PROSITE-ProRule annotation
Contains 3 WW domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0940. Eukaryota.
COG5021. LUCA.
GeneTreeiENSGT00760000118966.
HOGENOMiHOG000208451.
HOVERGENiHBG004134.
InParanoidiP46935.
KOiK10591.
OMAiYRRILSV.
OrthoDBiEOG091G0SS8.
PhylomeDBiP46935.
TreeFamiTF323658.

Family and domain databases

Gene3Di2.60.40.150. 1 hit.
InterProiIPR000008. C2_dom.
IPR000569. HECT_dom.
IPR001202. WW_dom.
[Graphical view]
PfamiPF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 3 hits.
[Graphical view]
SMARTiSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 3 hits.
[Graphical view]
SUPFAMiSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 3 hits.
SSF56204. SSF56204. 1 hit.
PROSITEiPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 3 hits.
PS50020. WW_DOMAIN_2. 3 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P46935-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSSDMAADES EAPVLSEDEV WEFCLDKTED GGGSPGSDVT DTCEPPCGCW
60 70 80 90 100
ELNPNSLEEE HVLFTADPYL ELHNDDTRVV RVKVIAGIGL AKKDILGASD
110 120 130 140 150
PYVRVTLYDP MSGILTSVQT KTIKKSLNPK WNEEILFRVL PQRHRILFEV
160 170 180 190 200
FDENRLTRDD FLGQVDVPLY PLPTENPRME RPYTFKDFVL HPRSHKSRVK
210 220 230 240 250
GYLRLKMTYL PKNGSEDENA DQAEELEPGW VVLDQPDAAT HLPHPPEPSP
260 270 280 290 300
LPPGWEERQD VLGRTYYVNH ESRRTQWKRP SPDDDLTDED NDDMQLQAQR
310 320 330 340 350
AFTTRRQISE DVDGPDNRES PENWEIVRED ENTEYSGQAV QSPPSGHIDV
360 370 380 390 400
QTHLAEEFNT RLAVCGNPAT SQPVTSSNHS SRGGSLQTCI FEEQPTLPVL
410 420 430 440 450
LPTSSGLPPG WEEKQDDRGR SYYVDHNSKT TTWSKPTMQD DPRSKIPAHL
460 470 480 490 500
RGKTDSNDLG PLPPGWEERT HTDGRVFFIN HNIKKTQWED PRLQNVAITG
510 520 530 540 550
PAVPYSRDYK RKYEFFRRKL KKQTDIPNKF EMKLRRANIL EDSYRRIMGV
560 570 580 590 600
KRADLLKARL WIEFDGEKGL DYGGVAREWF FLISKEMFNP YYGLFEYSAT
610 620 630 640 650
DNYTLQINPN SGLCNEDHLS YFKFIGRVAG MAVYHGKLLD GFFIRPFYKM
660 670 680 690 700
MLQKLITLHD MESVDSEYYS SLRWILENDP TELDLRFIID EELFGQTHQH
710 720 730 740 750
ELKTGGSEIV VTNKNKKEYI YLVIQWRFVN RIQKQMAAFK EGFFELIPQD
760 770 780 790 800
LIKIFDENEL ELLMCGLGDV DVNDWREHTK YKNGYSMNHQ VIHWFWKAVW
810 820 830 840 850
MMDSEKRIRL LQFVTGTSRV PMNGFAELYG SNGPQSFTVE QWGTPDKLPR
860 870 880
AHTCFNRLDL PPYESFDELW DKLQMAIENT QGFDGVD
Length:887
Mass (Da):102,706
Last modified:June 20, 2003 - v3
Checksum:iAE7DD3ED63986C50
GO

Sequence cautioni

The sequence AAB63360 differs from that shown. Reason: Frameshift at position 12. Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D85414 mRNA. Translation: BAA12803.1.
U96635 mRNA. Translation: AAB63360.1. Frameshift.
AK088620 mRNA. Translation: BAC40458.1.
AK088767 mRNA. Translation: BAC40558.1.
AK122203 mRNA. Translation: BAC65485.1.
AK133838 mRNA. Translation: BAE21875.1.
CCDSiCCDS72275.1.
RefSeqiNP_035020.2. NM_010890.3.
UniGeneiMm.279923.

Genome annotation databases

EnsembliENSMUST00000034740; ENSMUSP00000034740; ENSMUSG00000032216.
GeneIDi17999.
KEGGimmu:17999.
UCSCiuc009qqe.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D85414 mRNA. Translation: BAA12803.1.
U96635 mRNA. Translation: AAB63360.1. Frameshift.
AK088620 mRNA. Translation: BAC40458.1.
AK088767 mRNA. Translation: BAC40558.1.
AK122203 mRNA. Translation: BAC65485.1.
AK133838 mRNA. Translation: BAE21875.1.
CCDSiCCDS72275.1.
RefSeqiNP_035020.2. NM_010890.3.
UniGeneiMm.279923.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3M7FX-ray2.00B71-246[»]
ProteinModelPortaliP46935.
SMRiP46935. Positions 71-246, 250-281, 406-883.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi201723. 50 interactions.
DIPiDIP-32323N.
IntActiP46935. 16 interactions.
MINTiMINT-90132.
STRINGi10090.ENSMUSP00000034740.

PTM databases

iPTMnetiP46935.
PhosphoSiteiP46935.
SwissPalmiP46935.

Proteomic databases

EPDiP46935.
MaxQBiP46935.
PaxDbiP46935.
PRIDEiP46935.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000034740; ENSMUSP00000034740; ENSMUSG00000032216.
GeneIDi17999.
KEGGimmu:17999.
UCSCiuc009qqe.1. mouse.

Organism-specific databases

CTDi4734.
MGIiMGI:97297. Nedd4.
RougeiSearch...

Phylogenomic databases

eggNOGiKOG0940. Eukaryota.
COG5021. LUCA.
GeneTreeiENSGT00760000118966.
HOGENOMiHOG000208451.
HOVERGENiHBG004134.
InParanoidiP46935.
KOiK10591.
OMAiYRRILSV.
OrthoDBiEOG091G0SS8.
PhylomeDBiP46935.
TreeFamiTF323658.

Enzyme and pathway databases

UniPathwayiUPA00143.
ReactomeiR-MMU-1169408. ISG15 antiviral mechanism.
R-MMU-1253288. Downregulation of ERBB4 signaling.

Miscellaneous databases

ChiTaRSiNedd4. mouse.
PROiP46935.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000032216.
ExpressionAtlasiP46935. baseline and differential.
GenevisibleiP46935. MM.

Family and domain databases

Gene3Di2.60.40.150. 1 hit.
InterProiIPR000008. C2_dom.
IPR000569. HECT_dom.
IPR001202. WW_dom.
[Graphical view]
PfamiPF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 3 hits.
[Graphical view]
SMARTiSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 3 hits.
[Graphical view]
SUPFAMiSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 3 hits.
SSF56204. SSF56204. 1 hit.
PROSITEiPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 3 hits.
PS50020. WW_DOMAIN_2. 3 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiNEDD4_MOUSE
AccessioniPrimary (citable) accession number: P46935
Secondary accession number(s): O08758, Q3UZI2, Q8BGB3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: June 20, 2003
Last modified: September 7, 2016
This is version 166 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

A cysteine residue is required for ubiquitin-thioester formation.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.