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P46934

- NEDD4_HUMAN

UniProt

P46934 - NEDD4_HUMAN

Protein

E3 ubiquitin-protein ligase NEDD4

Gene

NEDD4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 151 (01 Oct 2014)
      Sequence version 4 (30 Nov 2010)
      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. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. 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. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. 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. Involved in the ubiquitination of ebola virus VP40 protein and this ubiquitination plays a role in facilitating viral budding.7 Publications

    Enzyme regulationi

    Activated by NDFIP1- and NDFIP2-binding.By similarity

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei1286 – 12861Glycyl thioester intermediatePROSITE-ProRule annotation

    GO - Molecular functioni

    1. beta-2 adrenergic receptor binding Source: UniProtKB
    2. ligase activity Source: UniProtKB-KW
    3. phosphoserine binding Source: BHF-UCL
    4. phosphothreonine binding Source: BHF-UCL
    5. proline-rich region binding Source: UniProtKB
    6. protein binding Source: UniProtKB
    7. protein domain specific binding Source: UniProtKB
    8. RNA polymerase binding Source: BHF-UCL
    9. sodium channel inhibitor activity Source: BHF-UCL
    10. ubiquitin binding Source: BHF-UCL
    11. ubiquitin-protein transferase activity Source: BHF-UCL

    GO - Biological processi

    1. adaptive immune response Source: Ensembl
    2. blood vessel morphogenesis Source: Ensembl
    3. cellular response to UV Source: BHF-UCL
    4. cytokine-mediated signaling pathway Source: Reactome
    5. development involved in symbiotic interaction Source: UniProtKB
    6. endocardial cushion development Source: Ensembl
    7. glucocorticoid receptor signaling pathway Source: BHF-UCL
    8. lysosomal transport Source: UniProtKB
    9. negative regulation of sodium ion transport Source: UniProtKB
    10. negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage Source: BHF-UCL
    11. negative regulation of vascular endothelial growth factor receptor signaling pathway Source: UniProtKB
    12. neuromuscular junction development Source: Ensembl
    13. neuron projection development Source: BHF-UCL
    14. outflow tract morphogenesis Source: Ensembl
    15. positive regulation of nucleocytoplasmic transport Source: BHF-UCL
    16. positive regulation of phosphatidylinositol 3-kinase signaling Source: BHF-UCL
    17. positive regulation of protein catabolic process Source: MGI
    18. progesterone receptor signaling pathway Source: BHF-UCL
    19. protein K63-linked ubiquitination Source: UniProtKB
    20. protein monoubiquitination Source: Ensembl
    21. protein targeting to lysosome Source: UniProtKB
    22. protein ubiquitination Source: UniProtKB
    23. protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: BHF-UCL
    24. receptor catabolic process Source: UniProtKB
    25. receptor internalization Source: UniProtKB
    26. regulation of dendrite morphogenesis Source: UniProtKB
    27. regulation of ion transmembrane transport Source: BHF-UCL
    28. regulation of membrane potential Source: BHF-UCL
    29. regulation of potassium ion transmembrane transporter activity Source: BHF-UCL
    30. regulation of synapse organization Source: Ensembl
    31. response to calcium ion Source: BHF-UCL
    32. T cell activation Source: Ensembl
    33. transmission of virus Source: BHF-UCL
    34. ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway Source: BHF-UCL

    Keywords - Molecular functioni

    Ligase

    Keywords - Biological processi

    Host-virus interaction, Neurogenesis, Ubl conjugation pathway

    Enzyme and pathway databases

    ReactomeiREACT_115828. Downregulation of ERBB4 signaling.
    REACT_115831. ISG15 antiviral mechanism.
    REACT_75842. Antigen processing: Ubiquitination & Proteasome degradation.
    SignaLinkiP46934.
    UniPathwayiUPA00143.

    Protein family/group databases

    TCDBi8.A.30.1.2. the nedd4-family interacting protein-2 (nedd4) family.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    E3 ubiquitin-protein ligase NEDD4 (EC:6.3.2.-)
    Alternative name(s):
    Cell proliferation-inducing gene 53 protein
    Neural precursor cell expressed developmentally down-regulated protein 4
    Short name:
    NEDD-4
    Gene namesi
    Name:NEDD4
    Synonyms:KIAA0093, NEDD4-1
    ORF Names:PIG53
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 15

    Organism-specific databases

    HGNCiHGNC:7727. NEDD4.

    Subcellular locationi

    Cytoplasm By similarity. 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 similarity1 Publication

    GO - Cellular componenti

    1. apicolateral plasma membrane Source: BHF-UCL
    2. cell cortex Source: BHF-UCL
    3. chromatin Source: BHF-UCL
    4. cytoplasm Source: BHF-UCL
    5. cytosol Source: BHF-UCL
    6. Golgi apparatus Source: UniProtKB
    7. nucleus Source: RefGenome
    8. perinuclear region of cytoplasm Source: BHF-UCL
    9. plasma membrane Source: UniProtKB
    10. ubiquitin ligase complex Source: BHF-UCL

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane

    Pathology & Biotechi

    Organism-specific databases

    PharmGKBiPA31533.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 13191319E3 ubiquitin-protein ligase NEDD4PRO_0000120319Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei648 – 6481PhosphothreonineBy similarity
    Modified residuei670 – 6701PhosphoserineBy similarity
    Modified residuei747 – 7471Phosphoserine2 Publications

    Post-translational modificationi

    Auto-ubiquitinated.By similarity

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiP46934.
    PaxDbiP46934.
    PRIDEiP46934.

    PTM databases

    PhosphoSiteiP46934.

    Expressioni

    Gene expression databases

    BgeeiP46934.
    CleanExiHS_NEDD4.
    GenevestigatoriP46934.

    Organism-specific databases

    HPAiCAB001991.
    HPA039883.

    Interactioni

    Subunit structurei

    Interacts with UBE2D2. Binds SCNN1A, SCNN1B and SCNN1G. 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 and PRRG2 By similarity. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes By similarity. Interaction with PTEN is questionable according to PubMed:18562292. Interacts with viral proteins that contain a late- budding motif P-P-P-Y. This interaction is essential for viral particle budding of a lot of retroviruses, like HTLV-1 Gag and MLV Gag. Interacts (via C2 domain) with GRB10 (via SH2 domain). Interacts with ERBB4 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. Interacts with ISG15. Interacts (via WW domain) with RAPGEF2; this interaction leads to ubiquitination and degradation via the proteasome pathway.By similarity10 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    FGFR1P1136226EBI-726944,EBI-1028277
    GABARAPO951666EBI-726944,EBI-712001
    GABARAPL1Q9H0R86EBI-726944,EBI-746969
    GABARAPL2P605206EBI-726944,EBI-720116
    LITAFQ997324EBI-726944,EBI-725647
    PTENP604844EBI-726944,EBI-696162
    RNF11Q9Y3C52EBI-726944,EBI-396669
    SCNN1BP511684EBI-726944,EBI-2547187

    Protein-protein interaction databases

    BioGridi110811. 268 interactions.
    DIPiDIP-29815N.
    IntActiP46934. 27 interactions.
    MINTiMINT-86457.
    STRINGi9606.ENSP00000345530.

    Structurei

    Secondary structure

    1
    1319
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi520 – 5289
    Beta strandi546 – 5494
    Beta strandi561 – 5699
    Beta strandi846 – 8505
    Turni852 – 8543
    Beta strandi856 – 8605
    Turni861 – 8644
    Beta strandi865 – 8695
    Turni871 – 8733
    Helixi941 – 95111
    Beta strandi956 – 9583
    Beta strandi960 – 9667
    Helixi968 – 9703
    Helixi971 – 9799
    Helixi985 – 9895
    Beta strandi990 – 9967
    Helixi1004 – 101916
    Helixi1022 – 10243
    Beta strandi1025 – 10317
    Beta strandi1037 – 10393
    Helixi1043 – 10464
    Helixi1050 – 106617
    Beta strandi1071 – 10733
    Helixi1077 – 10837
    Helixi1090 – 10945
    Helixi1098 – 110912
    Helixi1113 – 11153
    Beta strandi1118 – 11258
    Beta strandi1128 – 11358
    Helixi1138 – 11403
    Turni1145 – 11473
    Helixi1148 – 116013
    Helixi1162 – 11643
    Helixi1165 – 117511
    Turni1176 – 11783
    Helixi1181 – 11844
    Helixi1189 – 11979
    Helixi1204 – 12096
    Beta strandi1211 – 12144
    Beta strandi1219 – 12213
    Helixi1222 – 123312
    Helixi1236 – 124712
    Beta strandi1248 – 12503
    Helixi1257 – 12593
    Beta strandi1263 – 12664
    Beta strandi1269 – 12735
    Beta strandi1282 – 12843
    Helixi1285 – 12873
    Beta strandi1289 – 12924
    Helixi1298 – 131013

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2KPZNMR-A834-878[»]
    2KQ0NMR-A834-878[»]
    2M3ONMR-W838-877[»]
    2XBBX-ray2.68A/B938-1319[»]
    2XBFX-ray2.50A938-1319[»]
    3B7YX-ray1.80A/B517-571[»]
    4BBNX-ray2.51A938-1319[»]
    4BE8X-ray3.00A938-1319[»]
    4N7FX-ray1.10A/B841-874[»]
    4N7HX-ray1.70A840-872[»]
    ProteinModelPortaliP46934.
    SMRiP46934. Positions 517-571, 611-642, 768-798, 841-873, 888-932, 938-1312.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP46934.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini610 – 64334WW 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini767 – 80034WW 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini840 – 87334WW 3PROSITE-ProRule annotationAdd
    BLAST
    Domaini892 – 92534WW 4PROSITE-ProRule annotationAdd
    BLAST
    Domaini984 – 1318335HECTPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni578 – 981404Mediates interaction with TNIKBy similarityAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi68 – 215148Ser-richAdd
    BLAST

    Domaini

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

    Sequence similaritiesi

    Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.PROSITE-ProRule annotation
    Contains 4 WW domains.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiCOG5021.
    HOVERGENiHBG004134.
    KOiK10591.
    OMAiRRICRAF.
    OrthoDBiEOG7RFTGT.
    PhylomeDBiP46934.
    TreeFamiTF323658.

    Family and domain databases

    Gene3Di2.60.40.150. 1 hit.
    InterProiIPR000008. C2_dom.
    IPR000569. HECT.
    IPR001202. WW_dom.
    [Graphical view]
    PfamiPF00632. HECT. 1 hit.
    PF00397. WW. 4 hits.
    [Graphical view]
    SMARTiSM00119. HECTc. 1 hit.
    SM00456. WW. 4 hits.
    [Graphical view]
    SUPFAMiSSF51045. SSF51045. 4 hits.
    SSF56204. SSF56204. 1 hit.
    PROSITEiPS50237. HECT. 1 hit.
    PS01159. WW_DOMAIN_1. 4 hits.
    PS50020. WW_DOMAIN_2. 4 hits.
    [Graphical view]

    Sequences (4)i

    Sequence statusi: Complete.

    This entry describes 4 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P46934-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MAQSLRLHFA ARRSNTYPLS ETSGDDLDSH VHMCFKRPTR ISTSNVVQMK     50
    LTPRQTALAP LIKENVQSQE RSSVPSSENV NKKSSCLQIS LQPTRYSGYL 100
    QSSNVLADSD DASFTCILKD GIYSSAVVDN ELNAVNDGHL VSSPAICSGS 150
    LSNFSTSDNG SYSSNGSDFG SCASITSGGS YTNSVISDSS SYTFPPSDDT 200
    FLGGNLPSDS TSNRSVPNRN TTPCEIFSRS TSTDPFVQDD LEHGLEIMKL 250
    PVSRNTKIPL KRYSSLVIFP RSPSTTRPTS PTSLCTLLSK GSYQTSHQFI 300
    ISPSEIAHNE DGTSAKGFLS TAVNGLRLSK TICTPGEVRD IRPLHRKGSL 350
    QKKIVLSNNT PRQTVCEKSS EGYSCVSVHF TQRKAATLDC ETTNGDCKPE 400
    MSEIKLNSDS EYIKLMHRTS ACLPSSQNVD CQININGELE RPHSQMNKNH 450
    GILRRSISLG GAYPNISCLS SLKHNCSKGG PSQLLIKFAS GNEGKVDNLS 500
    RDSNRDCTNE LSNSCKTRDD FLGQVDVPLY PLPTENPRLE RPYTFKDFVL 550
    HPRSHKSRVK GYLRLKMTYL PKTSGSEDDN AEQAEELEPG WVVLDQPDAA 600
    CHLQQQQEPS PLPPGWEERQ DILGRTYYVN HESRRTQWKR PTPQDNLTDA 650
    ENGNIQLQAQ RAFTTRRQIS EETESVDNRE SSENWEIIRE DEATMYSNQA 700
    FPSPPPSSNL DVPTHLAEEL NARLTIFGNS AVSQPASSSN HSSRRGSLQA 750
    YTFEEQPTLP VLLPTSSGLP PGWEEKQDER GRSYYVDHNS RTTTWTKPTV 800
    QATVETSQLT SSQSSAGPQS QASTSDSGQQ VTQPSEIEQG FLPKGWEVRH 850
    APNGRPFFID HNTKTTTWED PRLKIPAHLR GKTSLDTSND LGPLPPGWEE 900
    RTHTDGRIFY INHNIKRTQW EDPRLENVAI TGPAVPYSRD YKRKYEFFRR 950
    KLKKQNDIPN KFEMKLRRAT VLEDSYRRIM GVKRADFLKA RLWIEFDGEK 1000
    GLDYGGVARE WFFLISKEMF NPYYGLFEYS ATDNYTLQIN PNSGLCNEDH 1050
    LSYFKFIGRV AGMAVYHGKL LDGFFIRPFY KMMLHKPITL HDMESVDSEY 1100
    YNSLRWILEN DPTELDLRFI IDEELFGQTH QHELKNGGSE IVVTNKNKKE 1150
    YIYLVIQWRF VNRIQKQMAA FKEGFFELIP QDLIKIFDEN ELELLMCGLG 1200
    DVDVNDWREH TKYKNGYSAN HQVIQWFWKA VLMMDSEKRI RLLQFVTGTS 1250
    RVPMNGFAEL YGSNGPQSFT VEQWGTPEKL PRAHTCFNRL DLPPYESFEE 1300
    LWDKLQMAIE NTQGFDGVD 1319

    Note: No experimental confirmation available.

    Length:1,319
    Mass (Da):149,114
    Last modified:November 30, 2010 - v4
    Checksum:iD56EBBC50A34F13B
    GO
    Isoform 2 (identifier: P46934-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         589-604: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:1,303
    Mass (Da):147,384
    Checksum:iC40112E4C9BC8416
    GO
    Isoform 3 (identifier: P46934-3) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         517-588: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:1,247
    Mass (Da):140,696
    Checksum:i827AC55FB4AFB6A3
    GO
    Isoform 4 (identifier: P46934-4) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-419: Missing.
         420-516: SACLPSSQNV...CTNELSNSCK → MATCAVEVFG...LFEVFDENRL

    Show »
    Length:900
    Mass (Da):104,217
    Checksum:i4303287D3133B1C7
    GO

    Sequence cautioni

    The sequence BAA07655.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti59 – 591A → T in AL832063. (PubMed:17974005)Curated
    Sequence conflicti407 – 4071N → H in AL832063. (PubMed:17974005)Curated
    Sequence conflicti620 – 6201Q → R in AAT52215. 1 PublicationCurated
    Sequence conflicti620 – 6201Q → R in AAI44285. (PubMed:15489334)Curated
    Sequence conflicti863 – 8631T → I in AAI36606. (PubMed:15489334)Curated
    Sequence conflicti863 – 8631T → I in AAI44285. (PubMed:15489334)Curated
    Sequence conflicti1199 – 11991L → P in BAG65229. (PubMed:14702039)Curated
    Sequence conflicti1268 – 12681S → L in AL832063. (PubMed:17974005)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti33 – 331M → V.
    Corresponds to variant rs1912403 [ dbSNP | Ensembl ].
    VAR_061985
    Natural varianti627 – 6271Y → H in a breast cancer sample; somatic mutation. 1 Publication
    VAR_036472
    Natural varianti679 – 6791R → Q.5 Publications
    Corresponds to variant rs2303580 [ dbSNP | Ensembl ].
    VAR_047909
    Natural varianti698 – 6981N → S.5 Publications
    Corresponds to variant rs2303579 [ dbSNP | Ensembl ].
    VAR_047910

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 419419Missing in isoform 4. 4 PublicationsVSP_038256Add
    BLAST
    Alternative sequencei420 – 51697SACLP…SNSCK → MATCAVEVFGLLEDEENSRI VRVRVIAGIGLAKKDILGAS DPYVRVTLYDPMNGVLTSVQ TKTIKKSLNPKWNEEILFRV HPQQHRLLFEVFDENRL in isoform 4. 4 PublicationsVSP_038257Add
    BLAST
    Alternative sequencei517 – 58872Missing in isoform 3. 1 PublicationVSP_038258Add
    BLAST
    Alternative sequencei589 – 60416Missing in isoform 2. 1 PublicationVSP_038259Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D42055 mRNA. Translation: BAA07655.1. Different initiation.
    AK304394 mRNA. Translation: BAG65229.1.
    AY550969 mRNA. Translation: AAT52215.1.
    AL832063 Genomic DNA. No translation available.
    AC009997 Genomic DNA. No translation available.
    AC039057 Genomic DNA. No translation available.
    CH471082 Genomic DNA. Translation: EAW77495.1.
    BC136605 mRNA. Translation: AAI36606.1.
    BC144284 mRNA. Translation: AAI44285.1.
    BC144285 mRNA. Translation: AAI44286.1.
    BC152452 mRNA. Translation: AAI52453.1.
    BC152562 mRNA. Translation: AAI52563.1.
    CCDSiCCDS10156.1. [P46934-3]
    CCDS45265.1. [P46934-4]
    CCDS61643.1. [P46934-2]
    CCDS61644.1. [P46934-1]
    RefSeqiNP_001271267.1. NM_001284338.1. [P46934-1]
    NP_001271268.1. NM_001284339.1. [P46934-2]
    NP_001271269.1. NM_001284340.1.
    NP_006145.2. NM_006154.3. [P46934-4]
    NP_940682.2. NM_198400.3. [P46934-3]
    UniGeneiHs.1565.

    Genome annotation databases

    EnsembliENST00000338963; ENSP00000345530; ENSG00000069869. [P46934-3]
    ENST00000435532; ENSP00000410613; ENSG00000069869. [P46934-4]
    ENST00000506154; ENSP00000422705; ENSG00000069869. [P46934-2]
    ENST00000508342; ENSP00000424827; ENSG00000069869. [P46934-1]
    GeneIDi4734.
    KEGGihsa:4734.
    UCSCiuc002adi.3. human. [P46934-3]
    uc002adj.3. human. [P46934-1]
    uc002adl.3. human. [P46934-4]
    uc010ugj.2. human. [P46934-2]

    Polymorphism databases

    DMDMi313104311.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D42055 mRNA. Translation: BAA07655.1 . Different initiation.
    AK304394 mRNA. Translation: BAG65229.1 .
    AY550969 mRNA. Translation: AAT52215.1 .
    AL832063 Genomic DNA. No translation available.
    AC009997 Genomic DNA. No translation available.
    AC039057 Genomic DNA. No translation available.
    CH471082 Genomic DNA. Translation: EAW77495.1 .
    BC136605 mRNA. Translation: AAI36606.1 .
    BC144284 mRNA. Translation: AAI44285.1 .
    BC144285 mRNA. Translation: AAI44286.1 .
    BC152452 mRNA. Translation: AAI52453.1 .
    BC152562 mRNA. Translation: AAI52563.1 .
    CCDSi CCDS10156.1. [P46934-3 ]
    CCDS45265.1. [P46934-4 ]
    CCDS61643.1. [P46934-2 ]
    CCDS61644.1. [P46934-1 ]
    RefSeqi NP_001271267.1. NM_001284338.1. [P46934-1 ]
    NP_001271268.1. NM_001284339.1. [P46934-2 ]
    NP_001271269.1. NM_001284340.1.
    NP_006145.2. NM_006154.3. [P46934-4 ]
    NP_940682.2. NM_198400.3. [P46934-3 ]
    UniGenei Hs.1565.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2KPZ NMR - A 834-878 [» ]
    2KQ0 NMR - A 834-878 [» ]
    2M3O NMR - W 838-877 [» ]
    2XBB X-ray 2.68 A/B 938-1319 [» ]
    2XBF X-ray 2.50 A 938-1319 [» ]
    3B7Y X-ray 1.80 A/B 517-571 [» ]
    4BBN X-ray 2.51 A 938-1319 [» ]
    4BE8 X-ray 3.00 A 938-1319 [» ]
    4N7F X-ray 1.10 A/B 841-874 [» ]
    4N7H X-ray 1.70 A 840-872 [» ]
    ProteinModelPortali P46934.
    SMRi P46934. Positions 517-571, 611-642, 768-798, 841-873, 888-932, 938-1312.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 110811. 268 interactions.
    DIPi DIP-29815N.
    IntActi P46934. 27 interactions.
    MINTi MINT-86457.
    STRINGi 9606.ENSP00000345530.

    Protein family/group databases

    TCDBi 8.A.30.1.2. the nedd4-family interacting protein-2 (nedd4) family.

    PTM databases

    PhosphoSitei P46934.

    Polymorphism databases

    DMDMi 313104311.

    Proteomic databases

    MaxQBi P46934.
    PaxDbi P46934.
    PRIDEi P46934.

    Protocols and materials databases

    DNASUi 4734.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000338963 ; ENSP00000345530 ; ENSG00000069869 . [P46934-3 ]
    ENST00000435532 ; ENSP00000410613 ; ENSG00000069869 . [P46934-4 ]
    ENST00000506154 ; ENSP00000422705 ; ENSG00000069869 . [P46934-2 ]
    ENST00000508342 ; ENSP00000424827 ; ENSG00000069869 . [P46934-1 ]
    GeneIDi 4734.
    KEGGi hsa:4734.
    UCSCi uc002adi.3. human. [P46934-3 ]
    uc002adj.3. human. [P46934-1 ]
    uc002adl.3. human. [P46934-4 ]
    uc010ugj.2. human. [P46934-2 ]

    Organism-specific databases

    CTDi 4734.
    GeneCardsi GC15M056119.
    HGNCi HGNC:7727. NEDD4.
    HPAi CAB001991.
    HPA039883.
    MIMi 602278. gene.
    neXtProti NX_P46934.
    PharmGKBi PA31533.
    HUGEi Search...
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG5021.
    HOVERGENi HBG004134.
    KOi K10591.
    OMAi RRICRAF.
    OrthoDBi EOG7RFTGT.
    PhylomeDBi P46934.
    TreeFami TF323658.

    Enzyme and pathway databases

    UniPathwayi UPA00143 .
    Reactomei REACT_115828. Downregulation of ERBB4 signaling.
    REACT_115831. ISG15 antiviral mechanism.
    REACT_75842. Antigen processing: Ubiquitination & Proteasome degradation.
    SignaLinki P46934.

    Miscellaneous databases

    ChiTaRSi NEDD4. human.
    EvolutionaryTracei P46934.
    GeneWikii NEDD4.
    GenomeRNAii 4734.
    NextBioi 18250.
    PROi P46934.
    SOURCEi Search...

    Gene expression databases

    Bgeei P46934.
    CleanExi HS_NEDD4.
    Genevestigatori P46934.

    Family and domain databases

    Gene3Di 2.60.40.150. 1 hit.
    InterProi IPR000008. C2_dom.
    IPR000569. HECT.
    IPR001202. WW_dom.
    [Graphical view ]
    Pfami PF00632. HECT. 1 hit.
    PF00397. WW. 4 hits.
    [Graphical view ]
    SMARTi SM00119. HECTc. 1 hit.
    SM00456. WW. 4 hits.
    [Graphical view ]
    SUPFAMi SSF51045. SSF51045. 4 hits.
    SSF56204. SSF56204. 1 hit.
    PROSITEi PS50237. HECT. 1 hit.
    PS01159. WW_DOMAIN_1. 4 hits.
    PS50020. WW_DOMAIN_2. 4 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, UBIQUITIN LIGASE ACTIVITY, INTERACTION WITH PTEN.
    2. "Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1."
      Nagase T., Miyajima N., Tanaka A., Sazuka T., Seki N., Sato S., Tabata S., Ishikawa K., Kawarabayasi Y., Kotani H., Nomura N.
      DNA Res. 2:37-43(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), VARIANTS GLN-679 AND SER-698.
      Tissue: Bone marrow.
    3. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), VARIANTS GLN-679 AND SER-698.
      Tissue: Trachea.
    4. "Identification of a human cell proliferation inducing gene."
      Kim J.W.
      Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), VARIANTS GLN-679 AND SER-698.
    5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
      Tissue: Adipose tissue.
    6. "Analysis of the DNA sequence and duplication history of human chromosome 15."
      Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A.
      , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.
      Nature 440:671-675(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANTS GLN-679 AND SER-698.
    7. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    8. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 4), VARIANTS GLN-679 AND SER-698.
      Tissue: Brain and Testis.
    9. "Nedd4 regulates ubiquitination and stability of the guanine-nucleotide exchange factor CNrasGEF."
      Pham N., Rotin D.
      J. Biol. Chem. 276:46995-47003(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH RAPGEF2.
    10. "PPPYVEPTAP motif is the late domain of human T-cell leukemia virus type 1 Gag and mediates its functional interaction with cellular proteins Nedd4 and Tsg101."
      Bouamr F., Melillo J.A., Wang M.Q., Nagashima K., de Los Santos M., Rein A., Goff S.P.
      J. Virol. 77:11882-11895(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH HTLV-1 MATRIX PROTEIN P19.
    11. "Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins."
      Putz U., Howitt J., Lackovic J., Foot N., Kumar S., Silke J., Tan S.S.
      J. Biol. Chem. 283:32621-32627(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION.
    12. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-747, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    13. "ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity."
      Okumura A., Pitha P.M., Harty R.N.
      Proc. Natl. Acad. Sci. U.S.A. 105:3974-3979(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH ISG15.
    14. "The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization."
      Fouladkou F., Landry T., Kawabe H., Neeb A., Lu C., Brose N., Stambolic V., Rotin D.
      Proc. Natl. Acad. Sci. U.S.A. 105:8585-8590(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH PTEN.
    15. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
      Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
      Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-747, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Leukemic T-cell.
    16. "HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK."
      Lin Q., Wang J., Childress C., Sudol M., Carey D.J., Yang W.
      Mol. Cell. Biol. 30:1541-1554(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH TNK2.
    17. Cited for: INTERACTION WITH RAP2A AND TNIK.
    18. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
      Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
      Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    19. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    20. "Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function."
      Persaud A., Alberts P., Hayes M., Guettler S., Clarke I., Sicheri F., Dirks P., Ciruna B., Rotin D.
      EMBO J. 30:3259-3273(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH FGFR1, FUNCTION IN UBIQUITINATION OF FGFR1.
    21. Cited for: INTERACTION WITH OTUD7B.
    22. "Crystal structure of the C2 domain of the E3 ubiquitin-protein ligase Nedd4."
      Structural genomics consortium (SGC)
      Submitted (OCT-2007) to the PDB data bank
      Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 1-152 (ISOFORM 4).
    23. "Human NEDD4 3rd WW domain complex with ebola Zaire virus matrix protein VP40 derived peptide."
      Iglesias-Bexiga M.
      Submitted (OCT-2009) to the PDB data bank
      Cited for: STRUCTURE BY NMR OF 834-878.
    24. "Human NEDD4 3rd WW domain complex with human T-cell leukemia virus GAP-Pro polyprotein derived peptide."
      Iglesias-Bexiga M., Luque I., Macias M.
      Submitted (OCT-2009) to the PDB data bank
      Cited for: STRUCTURE BY NMR OF 834-878.
    25. "Structure of the HECT:ubiquitin complex and its role in ubiquitin chain elongation."
      Maspero E., Mari S., Valentini E., Musacchio A., Fish A., Pasqualato S., Polo S.
      EMBO Rep. 12:342-349(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 938-1319 IN COMPLEX WITH UBIQUITIN, FUNCTION.
    26. Cited for: VARIANT [LARGE SCALE ANALYSIS] HIS-627.

    Entry informationi

    Entry nameiNEDD4_HUMAN
    AccessioniPrimary (citable) accession number: P46934
    Secondary accession number(s): A1KY35
    , A6ND72, A7MD29, B4E2R7, B7ZM59, B7ZM60, B9EGN5, D6RF89
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 1, 1995
    Last sequence update: November 30, 2010
    Last modified: October 1, 2014
    This is version 151 of the entry and version 4 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    A cysteine residue is required for ubiquitin-thioester formation.

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 15
      Human chromosome 15: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3