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Q62940

- NEDD4_RAT

UniProt

Q62940 - NEDD4_RAT

Protein

E3 ubiquitin-protein ligase NEDD4

Gene

Nedd4

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 118 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    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. 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.By similarity

    Enzyme regulationi

    Activated by NDFIP1- and NDFIP2-binding.By similarity

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei854 – 8541Glycyl thioester intermediatePROSITE-ProRule annotation

    GO - Molecular functioni

    1. ligase activity Source: UniProtKB-KW
    2. protein binding Source: RGD
    3. protein C-terminus binding Source: RGD
    4. ubiquitin-protein transferase activity Source: UniProtKB

    GO - Biological processi

    1. immune response Source: RGD
    2. negative regulation of vascular endothelial growth factor receptor signaling pathway Source: UniProtKB
    3. protein K63-linked ubiquitination Source: UniProtKB
    4. protein ubiquitination Source: UniProtKB
    5. protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: RefGenome
    6. regulation of dendrite morphogenesis Source: UniProtKB
    7. response to denervation involved in regulation of muscle adaptation Source: RGD

    Keywords - Molecular functioni

    Ligase

    Keywords - Biological processi

    Neurogenesis, Ubl conjugation pathway

    Enzyme and pathway databases

    UniPathwayiUPA00143.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    E3 ubiquitin-protein ligase NEDD4 (EC:6.3.2.-)
    Gene namesi
    Name:Nedd4
    Synonyms:Nedd4a
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Unplaced

    Organism-specific databases

    RGDi3157. Nedd4.

    Subcellular locationi

    Cytoplasm 1 Publication. Cell membrane By similarity; 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.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: RefGenome
    2. membrane raft Source: RGD
    3. microvillus Source: RGD
    4. nucleus Source: RefGenome
    5. plasma membrane Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 887887E3 ubiquitin-protein ligase NEDD4PRO_0000120321Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei284 – 2841PhosphothreonineBy similarity
    Modified residuei306 – 3061PhosphoserineBy similarity
    Modified residuei382 – 3821PhosphoserineBy similarity

    Post-translational modificationi

    Auto-ubiquitinated.By similarity

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Proteomic databases

    PaxDbiQ62940.
    PRIDEiQ62940.

    PTM databases

    PhosphoSiteiQ62940.

    Expressioni

    Tissue specificityi

    Ubiquitously expressed. Expression is highest in lung, kidney and brain.1 Publication

    Developmental stagei

    Down-regulated after synapse formation.1 Publication

    Gene expression databases

    GenevestigatoriQ62940.

    Interactioni

    Subunit structurei

    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.By similarity

    Protein-protein interaction databases

    BioGridi247522. 93 interactions.
    IntActiQ62940. 1 interaction.
    MINTiMINT-137690.
    STRINGi10116.ENSRNOP00000009747.

    Structurei

    Secondary structure

    1
    887
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi454 – 4563
    Beta strandi465 – 4695
    Beta strandi475 – 4795
    Turni480 – 4834
    Beta strandi484 – 4885
    Turni490 – 4923

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1I5HNMR-W452-499[»]
    ProteinModelPortaliQ62940.
    SMRiQ62940. Positions 70-208, 247-278, 401-435, 451-499, 505-878.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ62940.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini62 – 163102C2PROSITE-ProRule annotationAdd
    BLAST
    Domaini246 – 27934WW 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini402 – 43534WW 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini459 – 49234WW 3PROSITE-ProRule annotationAdd
    BLAST
    Domaini551 – 887337HECTPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni214 – 548335Mediates interaction with TNIKBy similarityAdd
    BLAST

    Domaini

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

    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

    eggNOGiCOG5021.
    HOGENOMiHOG000208451.
    HOVERGENiHBG004134.
    InParanoidiQ62940.
    KOiK10591.
    PhylomeDBiQ62940.

    Family and domain databases

    Gene3Di2.60.40.150. 1 hit.
    InterProiIPR000008. C2_dom.
    IPR024928. E3_ub_ligase_SMURF1.
    IPR000569. HECT.
    IPR001202. WW_dom.
    [Graphical view]
    PfamiPF00168. C2. 1 hit.
    PF00632. HECT. 1 hit.
    PF00397. WW. 3 hits.
    [Graphical view]
    PIRSFiPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
    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.

    Q62940-1 [UniParc]FASTAAdd to Basket

    « Hide

    MAADDTEAPV LSEDEVWEFC LDKNEEGGGS PGSDVTDTCE PPCGCWELNP    50
    SSLEEEHVLF TAESIISSFN NDDTRVVRVK VIAGIGLAKK DILGASDPYV 100
    RVTLYDPMSG VLTSVQTKTI KKSLNPKWNE EILFRVLPQQ HRILFEVFDE 150
    NRLTRDDFLG QVDVPLYPLP TENPRMERPY TFKDFVLHPR SHKSRVKGYL 200
    RLKMTYLPKN GSDDENADQA EELEPGWVVL DQPDAATHLQ HPPEPSPLPP 250
    GWEERQDVLG RTYYVNHESR TTQWKRPSPE DDLTDDENGD IQLQAHGAFT 300
    TRRQISEDVD GPDNHESPEN WEIVREDENT IYSGQAVQSP PSGHPDVQVR 350
    LAEELDTRLT MYGNPATSQP VTSSNHSSRG GSSQTCIFEE QPTLPVLLPT 400
    SSGLPPGWEE KQDDRGRSYY VDHNSKTTTW SKPTMQDDPR SKIPAHLRGK 450
    TPVDSNDLGP LPPGWEERTH TDGRVFFINH NIKKTQWEDP RMQNVAITGP 500
    AEPYSRDYKR KYEFFRRKLK KQTDIPNKFE MKLRRANILE DSYRRIMGVK 550
    RADFLKARLW IEFDGEKGLD YGGVAREWFF LISKEMFNPY YGLFEYSATE 600
    DNYTLQINPN SGLCNEDHLS YFKFIGRVAG MAVYHGKLLD GFFIRPFYKM 650
    MLQKLITLHD MESVDSEYYS SLRWILENDP TELDLRFIID EELFGQTHQH 700
    ELKTGGSEVV VTNKNKKEYI YLVIQWRFVN RIQKQMAAFK EGFFELIPQD 750
    LIKIFDENEL ELLMCGLGDV DVNDWREHTK YKNGYSLNHQ VIHWFWKAVL 800
    MMDSEKRIRL LQFVTGTSRV PMNGFAELYG SNGPQSFTVE QWGTPDKLPR 850
    AHTCFNRLDL PPYESFDELW DKLQMAIENT QGFDGVD 887
    Length:887
    Mass (Da):102,395
    Last modified:November 1, 1996 - v1
    Checksum:iD74B1097688CD9A1
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U50842 mRNA. Translation: AAB48949.1.
    PIRiS70642.
    RefSeqiNP_037118.1. NM_012986.1.
    UniGeneiRn.99540.

    Genome annotation databases

    GeneIDi25489.
    KEGGirno:25489.
    UCSCiRGD:3157. rat.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U50842 mRNA. Translation: AAB48949.1 .
    PIRi S70642.
    RefSeqi NP_037118.1. NM_012986.1.
    UniGenei Rn.99540.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1I5H NMR - W 452-499 [» ]
    ProteinModelPortali Q62940.
    SMRi Q62940. Positions 70-208, 247-278, 401-435, 451-499, 505-878.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 247522. 93 interactions.
    IntActi Q62940. 1 interaction.
    MINTi MINT-137690.
    STRINGi 10116.ENSRNOP00000009747.

    PTM databases

    PhosphoSitei Q62940.

    Proteomic databases

    PaxDbi Q62940.
    PRIDEi Q62940.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    GeneIDi 25489.
    KEGGi rno:25489.
    UCSCi RGD:3157. rat.

    Organism-specific databases

    CTDi 4734.
    RGDi 3157. Nedd4.

    Phylogenomic databases

    eggNOGi COG5021.
    HOGENOMi HOG000208451.
    HOVERGENi HBG004134.
    InParanoidi Q62940.
    KOi K10591.
    PhylomeDBi Q62940.

    Enzyme and pathway databases

    UniPathwayi UPA00143 .

    Miscellaneous databases

    EvolutionaryTracei Q62940.
    NextBioi 606851.
    PROi Q62940.

    Gene expression databases

    Genevestigatori Q62940.

    Family and domain databases

    Gene3Di 2.60.40.150. 1 hit.
    InterProi IPR000008. C2_dom.
    IPR024928. E3_ub_ligase_SMURF1.
    IPR000569. HECT.
    IPR001202. WW_dom.
    [Graphical view ]
    Pfami PF00168. C2. 1 hit.
    PF00632. HECT. 1 hit.
    PF00397. WW. 3 hits.
    [Graphical view ]
    PIRSFi PIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
    SMARTi SM00239. C2. 1 hit.
    SM00119. HECTc. 1 hit.
    SM00456. WW. 3 hits.
    [Graphical view ]
    SUPFAMi SSF49562. SSF49562. 1 hit.
    SSF51045. SSF51045. 3 hits.
    SSF56204. SSF56204. 1 hit.
    PROSITEi PS50004. C2. 1 hit.
    PS50237. HECT. 1 hit.
    PS01159. WW_DOMAIN_1. 3 hits.
    PS50020. WW_DOMAIN_2. 3 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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. 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.

    Entry informationi

    Entry nameiNEDD4_RAT
    AccessioniPrimary (citable) accession number: Q62940
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 3, 2003
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 118 of the entry and version 1 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. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3