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Q62940 (NEDD4_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 115. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase NEDD4

EC=6.3.2.-
Gene names
Name:Nedd4
Synonyms:Nedd4a
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length887 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Promotes ubiquitination of RAPGEF2. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Is involved in ubiquitination of ERBB4 intracellular domain E4ICD. 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 By similarity. Ref.2

Enzyme regulation

Activated by NDFIP1- and NDFIP2-binding By similarity.

Pathway

Protein modification; protein ubiquitination.

Subunit structure

Interacts with UBE2D2. Binds, in vitro, through the WW2 and WW3 domains, to neural isoforms of ENAH that contain the PPSY motif. Interacts with BEAN1, LITAF, RNF11, WBP1, WBP2, TMEPAI, NDFIP1, and PRRG2 By similarity. Interacts (via C2 domain) with GRB10 (via SH2 domain) By similarity. Binds SCNN1A, SCNN1B and SCNN1G. Interacts with ERBB4. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes By similarity. Interacts with TNIK; the interaction is direct, allows the TNIK-dependent recruitment of RAP2A and its ubiquitination by NEDD4. 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 By similarity. Ref.1 Ref.2 Ref.3

Subcellular location

Cytoplasm. Cell membrane; Peripheral membrane protein By similarity. 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. Ref.2

Tissue specificity

Ubiquitously expressed. Expression is highest in lung, kidney and brain. Ref.2

Developmental stage

Down-regulated after synapse formation. Ref.2

Domain

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

Post-translational modification

Auto-ubiquitinated By similarity.

Miscellaneous

A cysteine residue is required for ubiquitin-thioester formation.

Sequence similarities

Contains 1 C2 domain.

Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.

Contains 3 WW domains.

Ontologies

Keywords
   Biological processNeurogenesis
Ubl conjugation pathway
   Cellular componentCell membrane
Cytoplasm
Membrane
   DomainRepeat
   Molecular functionLigase
   PTMPhosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processimmune response

Inferred from expression pattern PubMed 11248052. Source: RGD

negative regulation of vascular endothelial growth factor receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

protein K63-linked ubiquitination

Inferred from direct assay Ref.2. Source: UniProtKB

protein ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein ubiquitination involved in ubiquitin-dependent protein catabolic process

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of dendrite morphogenesis

Inferred from direct assay Ref.2. Source: UniProtKB

response to denervation involved in regulation of muscle adaptation

Inferred from expression pattern PubMed 19125695. Source: RGD

   Cellular_componentcytoplasm

Inferred from Biological aspect of Ancestor. Source: RefGenome

membrane raft

Inferred from direct assay PubMed 11248052. Source: RGD

microvillus

Inferred from direct assay PubMed 9227416. Source: RGD

nucleus

Inferred from Biological aspect of Ancestor. Source: RefGenome

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionprotein C-terminus binding

Inferred from direct assay PubMed 9923703. Source: RGD

ubiquitin-protein ligase activity

Inferred from direct assay Ref.2. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 887887E3 ubiquitin-protein ligase NEDD4
PRO_0000120321

Regions

Domain62 – 163102C2
Domain246 – 27934WW 1
Domain402 – 43534WW 2
Domain459 – 49234WW 3
Domain551 – 887337HECT
Region214 – 548335Mediates interaction with TNIK By similarity

Sites

Active site8541Glycyl thioester intermediate By similarity

Amino acid modifications

Modified residue2841Phosphothreonine By similarity
Modified residue3061Phosphoserine By similarity
Modified residue3821Phosphoserine By similarity

Secondary structure

........... 887
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q62940 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: D74B1097688CD9A1

FASTA887102,395
        10         20         30         40         50         60 
MAADDTEAPV LSEDEVWEFC LDKNEEGGGS PGSDVTDTCE PPCGCWELNP SSLEEEHVLF 

        70         80         90        100        110        120 
TAESIISSFN NDDTRVVRVK VIAGIGLAKK DILGASDPYV RVTLYDPMSG VLTSVQTKTI 

       130        140        150        160        170        180 
KKSLNPKWNE EILFRVLPQQ HRILFEVFDE NRLTRDDFLG QVDVPLYPLP TENPRMERPY 

       190        200        210        220        230        240 
TFKDFVLHPR SHKSRVKGYL RLKMTYLPKN GSDDENADQA EELEPGWVVL DQPDAATHLQ 

       250        260        270        280        290        300 
HPPEPSPLPP GWEERQDVLG RTYYVNHESR TTQWKRPSPE DDLTDDENGD IQLQAHGAFT 

       310        320        330        340        350        360 
TRRQISEDVD GPDNHESPEN WEIVREDENT IYSGQAVQSP PSGHPDVQVR LAEELDTRLT 

       370        380        390        400        410        420 
MYGNPATSQP VTSSNHSSRG GSSQTCIFEE QPTLPVLLPT SSGLPPGWEE KQDDRGRSYY 

       430        440        450        460        470        480 
VDHNSKTTTW SKPTMQDDPR SKIPAHLRGK TPVDSNDLGP LPPGWEERTH TDGRVFFINH 

       490        500        510        520        530        540 
NIKKTQWEDP RMQNVAITGP AEPYSRDYKR KYEFFRRKLK KQTDIPNKFE MKLRRANILE 

       550        560        570        580        590        600 
DSYRRIMGVK RADFLKARLW IEFDGEKGLD YGGVAREWFF LISKEMFNPY YGLFEYSATE 

       610        620        630        640        650        660 
DNYTLQINPN SGLCNEDHLS YFKFIGRVAG MAVYHGKLLD GFFIRPFYKM MLQKLITLHD 

       670        680        690        700        710        720 
MESVDSEYYS SLRWILENDP TELDLRFIID EELFGQTHQH ELKTGGSEVV VTNKNKKEYI 

       730        740        750        760        770        780 
YLVIQWRFVN RIQKQMAAFK EGFFELIPQD LIKIFDENEL ELLMCGLGDV DVNDWREHTK 

       790        800        810        820        830        840 
YKNGYSLNHQ VIHWFWKAVL MMDSEKRIRL LQFVTGTSRV PMNGFAELYG SNGPQSFTVE 

       850        860        870        880 
QWGTPDKLPR AHTCFNRLDL PPYESFDELW DKLQMAIENT QGFDGVD 

« Hide

References

[1]"WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome."
Staub O., Dho S., Henry P., Correa J., Ishikawa T., McGlade J., Rotin D.
EMBO J. 15:2371-2380(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G.
Tissue: Lung.
[2]"Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development."
Kawabe H., Neeb A., Dimova K., Young S.M. Jr., Takeda M., Katsurabayashi S., Mitkovski M., Malakhova O.A., Zhang D.E., Umikawa M., Kariya K., Goebbels S., Nave K.A., Rosenmund C., Jahn O., Rhee J., Brose N.
Neuron 65:358-372(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH RAP2A AND TNIK, SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, TISSUE SPECIFICITY.
[3]"Solution structure of a Nedd4 WW domain-ENaC peptide complex."
Kanelis V., Rotin D., Forman-Kay J.D.
Nat. Struct. Biol. 8:407-412(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 452-499 IN COMPLEX WITH SCNN1B, INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U50842 mRNA. Translation: AAB48949.1.
PIRS70642.
RefSeqNP_037118.1. NM_012986.1.
UniGeneRn.99540.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1I5HNMR-W452-499[»]
ProteinModelPortalQ62940.
SMRQ62940. Positions 70-208, 247-278, 401-435, 451-499, 505-878.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid247522. 93 interactions.
IntActQ62940. 1 interaction.
MINTMINT-137690.
STRING10116.ENSRNOP00000009747.

PTM databases

PhosphoSiteQ62940.

Proteomic databases

PaxDbQ62940.
PRIDEQ62940.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID25489.
KEGGrno:25489.
UCSCRGD:3157. rat.

Organism-specific databases

CTD4734.
RGD3157. Nedd4.

Phylogenomic databases

eggNOGCOG5021.
HOGENOMHOG000208451.
HOVERGENHBG004134.
InParanoidQ62940.
KOK10591.
PhylomeDBQ62940.

Enzyme and pathway databases

UniPathwayUPA00143.

Gene expression databases

GenevestigatorQ62940.

Family and domain databases

Gene3D2.60.40.150. 1 hit.
InterProIPR000008. C2_dom.
IPR024928. E3_ub_ligase_SMURF1.
IPR000569. HECT.
IPR001202. WW_dom.
[Graphical view]
PfamPF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 3 hits.
[Graphical view]
PIRSFPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
SMARTSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 3 hits.
[Graphical view]
SUPFAMSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 3 hits.
SSF56204. SSF56204. 1 hit.
PROSITEPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 3 hits.
PS50020. WW_DOMAIN_2. 3 hits.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ62940.
NextBio606851.
PROQ62940.

Entry information

Entry nameNEDD4_RAT
AccessionPrimary (citable) accession number: Q62940
Entry history
Integrated into UniProtKB/Swiss-Prot: July 3, 2003
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 115 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways