Q8CFI0 (NED4L_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified
May 1, 2013.
Version 105.
History...
Names·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order
Names·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize orderNames and origin
| Protein names | Recommended name: E3 ubiquitin-protein ligase NEDD4-like EC=6.3.2.- Alternative name(s): NEDD4.2 Nedd4-2 | ||||
| Gene names |
| ||||
| Organism | Mus musculus (Mouse) [Reference proteome] | ||||
| Taxonomic identifier | 10090 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus![]() |
Protein attributes
| Sequence length | 1004 AA. |
| Sequence status | Complete. |
| Protein existence | Evidence 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. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2. Ref.1 Ref.2 Ref.5 Ref.6 Ref.8 |
| Enzyme regulation | Activated by NDFIP1- and NDFIP2-binding By similarity. Interacts with SGK1 By similarity. |
| Pathway | |
| Subunit structure | Interacts with SMAD2, SMAD3, SMAD6 and SMAD7. Interacts with CLCN5. The phosphorylated form interacts with 14-3-3 proteins. Interacts with NDIF1P in vitro By similarity. Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A and SCN10A. Interacts with UBE2E3. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase. Interacts with TNK2 By similarity. Interacts (via C2 domain) with NPC2 By similarity. Ref.2 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 |
| Subcellular location | |
| Tissue specificity | Highly expressed in liver and kidney. Also expressed in heart, brain and lung. Isoform 1 is expressed in kidney, lung and gut. Isoform 3 is ubiquitously expressed. Ref.1 Ref.6 |
| Post-translational modification | Phosphorylated; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation By similarity. Aldosterone induces Ser-477 phosphorylation by SGK1. Ref.5 Ref.10 Auto-ubiquitinated By similarity. |
| Sequence similarities | Contains 1 C2 domain. Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. Contains 4 WW domains. |
| Sequence caution | The sequence BAC31307.1 differs from that shown. Reason: Erroneous initiation. |
Ontologies
Alternative products
| This entry describes 3 isoforms produced by alternative splicing. [Align] [Select] | ||||||
| Isoform 1 (identifier: Q8CFI0-1) 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. | ||||||
| Isoform 2 (identifier: Q8CFI0-2) The sequence of this isoform differs from the canonical sequence as follows: 1-149: Missing. | ||||||
| Isoform 3 (identifier: Q8CFI0-3) The sequence of this isoform differs from the canonical sequence as follows: 385-404: Missing. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | |||||||||||||||||||||||||||||
Molecule processing | ||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 1004 | 1004 | E3 ubiquitin-protein ligase NEDD4-like | PRO_0000120324 | ||||||||||||||||||||||||||||||
Regions | ||||||||||||||||||||||||||||||||||
| Domain | 35 – 137 | 103 | C2 | |||||||||||||||||||||||||||||||
| Domain | 221 – 254 | 34 | WW 1 | |||||||||||||||||||||||||||||||
| Domain | 414 – 447 | 34 | WW 2 | |||||||||||||||||||||||||||||||
| Domain | 526 – 559 | 34 | WW 3 | |||||||||||||||||||||||||||||||
| Domain | 577 – 610 | 34 | WW 4 | |||||||||||||||||||||||||||||||
| Domain | 669 – 1003 | 335 | HECT | |||||||||||||||||||||||||||||||
| Compositional bias | 321 – 324 | 4 | Poly-Pro | |||||||||||||||||||||||||||||||
Sites | ||||||||||||||||||||||||||||||||||
| Active site | 971 | 1 | Glycyl thioester intermediate | |||||||||||||||||||||||||||||||
Amino acid modifications | ||||||||||||||||||||||||||||||||||
| Modified residue | 331 | 1 | Phosphothreonine Ref.12 | |||||||||||||||||||||||||||||||
| Modified residue | 347 | 1 | Phosphothreonine By similarity | |||||||||||||||||||||||||||||||
| Modified residue | 371 | 1 | Phosphoserine; by WNK1 and WNK4 Ref.5 | |||||||||||||||||||||||||||||||
| Modified residue | 396 | 1 | Phosphothreonine; by SGK1 By similarity | |||||||||||||||||||||||||||||||
| Modified residue | 475 | 1 | Phosphoserine Ref.11 | |||||||||||||||||||||||||||||||
| Modified residue | 477 | 1 | Phosphoserine; by SGK1 Ref.5 Ref.10 Ref.12 | |||||||||||||||||||||||||||||||
| Modified residue | 478 | 1 | Phosphoserine; by WNK1 and WNK4 By similarity | |||||||||||||||||||||||||||||||
| Modified residue | 493 | 1 | Phosphoserine By similarity | |||||||||||||||||||||||||||||||
| Modified residue | 508 | 1 | Phosphoserine Ref.12 | |||||||||||||||||||||||||||||||
| Modified residue | 512 | 1 | Phosphoserine Ref.12 | |||||||||||||||||||||||||||||||
| Modified residue | 516 | 1 | Phosphoserine By similarity | |||||||||||||||||||||||||||||||
Natural variations | ||||||||||||||||||||||||||||||||||
| Alternative sequence | 1 – 149 | 149 | Missing in isoform 2. | VSP_015450 | ||||||||||||||||||||||||||||||
| Alternative sequence | 385 – 404 | 20 | Missing in isoform 3. | VSP_015453 | ||||||||||||||||||||||||||||||
Experimental info | ||||||||||||||||||||||||||||||||||
| Mutagenesis | 371 | 1 | S → A: Weakly reduces phosphorylation by SGK1. Ref.5 | |||||||||||||||||||||||||||||||
| Mutagenesis | 477 | 1 | S → A: Strongly reduces phosphorylation by SGK1. Ref.5 | |||||||||||||||||||||||||||||||
| Mutagenesis | 971 | 1 | C → S: Abolishes catalytic activity. Ref.1 | |||||||||||||||||||||||||||||||
| Sequence conflict | 179 | 1 | A → G in AAK00809. Ref.1 | |||||||||||||||||||||||||||||||
| Sequence conflict | 390 | 1 | R → G in AAK00809. Ref.1 | |||||||||||||||||||||||||||||||
| Sequence conflict | 403 | 1 | P → S in AAK00809. Ref.1 | |||||||||||||||||||||||||||||||
| Sequence conflict | 585 | 1 | E → G in AAK00809. Ref.1 | |||||||||||||||||||||||||||||||
| Sequence conflict | 832 | 1 | N → T in AAK00809. Ref.1 | |||||||||||||||||||||||||||||||
| Sequence conflict | 847 | 1 | N → D in AAK00809. Ref.1 | |||||||||||||||||||||||||||||||
| Sequence conflict | 949 | 1 | N → K in BAC31307. Ref.4 | |||||||||||||||||||||||||||||||
Secondary structure | ||||||||||||||||||||||||||||||||||
Helix Strand Turn | ||||||||||||||||||||||||||||||||||
| Beta strand | 227 – 231 | 5 | ||||||||||||||||||||||||||||||||
| Beta strand | 233 – 235 | 3 | ||||||||||||||||||||||||||||||||
| Beta strand | 237 – 241 | 5 | ||||||||||||||||||||||||||||||||
| Turn | 242 – 244 | 3 | ||||||||||||||||||||||||||||||||
| Beta strand | 247 – 250 | 4 | ||||||||||||||||||||||||||||||||
| Beta strand | 420 – 424 | 5 | ||||||||||||||||||||||||||||||||
| Beta strand | 426 – 428 | 3 | ||||||||||||||||||||||||||||||||
| Beta strand | 430 – 434 | 5 | ||||||||||||||||||||||||||||||||
| Turn | 435 – 438 | 4 | ||||||||||||||||||||||||||||||||
| Beta strand | 439 – 443 | 5 | ||||||||||||||||||||||||||||||||
| Beta strand | 532 – 536 | 5 | ||||||||||||||||||||||||||||||||
| Beta strand | 542 – 546 | 5 | ||||||||||||||||||||||||||||||||
| Turn | 547 – 550 | 4 | ||||||||||||||||||||||||||||||||
| Beta strand | 551 – 555 | 5 | ||||||||||||||||||||||||||||||||
| Helix | 557 – 559 | 3 | ||||||||||||||||||||||||||||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel." Kamynina E., Debonneville C., Bens M., Vandewalle A., Staub O. FASEB J. 15:204-214(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY, FUNCTION, MUTAGENESIS OF CYS-971. Strain: C57BL/6. |
| [2] | "The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels." Fotia A.B., Dinudom A., Shearwin K.E., Koch J.-P., Korbmacher C., Cook D.I., Kumar S. FASEB J. 17:70-72(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G, FUNCTION. Tissue: Brain. |
| [3] | "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] (ISOFORM 2). Strain: FVB/N. Tissue: Kidney and Mammary gland. |
| [4] | "The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. Hayashizaki Y.Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 44-1004 (ISOFORM 3). Strain: C57BL/6J. Tissue: Cerebellum. |
| [5] | "Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression." Debonneville C., Flores S.Y., Kamynina E., Plant P.J., Tauxe C., Thomas M.A., Muenster C., Chraiebi A., Pratt J.H., Horisberger J.-D., Pearce D., Loffing J., Staub O. EMBO J. 20:7052-7059(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G, PHOSPHORYLATION AT SER-371 AND SER-477, MUTAGENESIS OF SER-371 AND SER-477. |
| [6] | "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel." Harvey K.F., Dinudom A., Cook D.I., Kumar S. J. Biol. Chem. 276:8597-8601(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G, TISSUE SPECIFICITY. |
| [7] | "Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein." Konstas A.-A., Shearwin-Whyatt L.M., Fotia A.B., Degger B., Riccardi D., Cook D.I., Korbmacher C., Kumar S. J. Biol. Chem. 277:29406-29416(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NDFIP2, SUBCELLULAR LOCATION. |
| [8] | "Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2." Fotia A.B., Ekberg J., Adams D.J., Cook D.I., Poronnik P., Kumar S. J. Biol. Chem. 279:28930-28935(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SCN1A; SCN2A; SCN3A; SCN5A; SCN8A; SCN9A; SCN10A; SCNN1A; SCNN1B AND SCNN1G. |
| [9] | "Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial Na+ channel." Debonneville C., Staub O. Mol. Cell. Biol. 24:2397-2409(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH UBE2E3. |
| [10] | "Aldosterone-induced serum and glucocorticoid-induced kinase 1 expression is accompanied by nedd4-2 phosphorylation and increased na+ transport in cortical collecting duct cells." Flores S.Y., Loffing-Cueni D., Kamynina E., Daidie D., Gerbex C., Chabanel S., Dudler J., Loffing J., Staub O. J. Am. Soc. Nephrol. 16:2279-2287(2005) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-477. |
| [11] | "Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations." Munton R.P., Tweedie-Cullen R., Livingstone-Zatchej M., Weinandy F., Waidelich M., Longo D., Gehrig P., Potthast F., Rutishauser D., Gerrits B., Panse C., Schlapbach R., Mansuy I.M. Mol. Cell. Proteomics 6:283-293(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-475, MASS SPECTROMETRY. Tissue: Brain cortex. |
| [12] | "Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-331; SER-477; SER-508 AND SER-512, MASS SPECTROMETRY. Tissue: Liver. |
| [13] | "Solution structures of WW domains of NEDD4-2." Kowalski K., Merkel A.L., Booker G.W. Submitted (OCT-2005) to the PDB data bank Cited for: STRUCTURE BY NMR OF 221-254; 414-447 AND 525-560. |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| EMBL GenBank DDBJ | AF277232 mRNA. Translation: AAK00809.1. BC039746 mRNA. Translation: AAH39746.1. BC071210 mRNA. Translation: AAH71210.1. AK042621 mRNA. Translation: BAC31307.1. Different initiation. | ||||||||||||||||||||||||
| IPI | IPI00404545. IPI00649115. IPI01008452. | ||||||||||||||||||||||||
| UniGene | Mm.98668. | ||||||||||||||||||||||||
3D structure databases | |||||||||||||||||||||||||
| PDBe RCSB PDB PDBj |
| ||||||||||||||||||||||||
| ProteinModelPortal | Q8CFI0. | ||||||||||||||||||||||||
| SMR | Q8CFI0. Positions 40-182, 221-254, 415-449, 525-995. | ||||||||||||||||||||||||
| ModBase | Search... | ||||||||||||||||||||||||
Protein-protein interaction databases | |||||||||||||||||||||||||
| DIP | DIP-48843N. | ||||||||||||||||||||||||
Protein family/group databases | |||||||||||||||||||||||||
| TCDB | 8.A.30.1.1. Nedd4-family interacting protein-2 (Nedd4) family. | ||||||||||||||||||||||||
PTM databases | |||||||||||||||||||||||||
| PhosphoSite | Q8CFI0. | ||||||||||||||||||||||||
Proteomic databases | |||||||||||||||||||||||||
| PaxDb | Q8CFI0. | ||||||||||||||||||||||||
| PRIDE | Q8CFI0. | ||||||||||||||||||||||||
Protocols and materials databases | |||||||||||||||||||||||||
| StructuralBiologyKnowledgebase | Search... | ||||||||||||||||||||||||
Genome annotation databases | |||||||||||||||||||||||||
| UCSC | uc008fen.2. mouse. uc008fer.2. mouse. uc012beb.1. mouse. | ||||||||||||||||||||||||
Organism-specific databases | |||||||||||||||||||||||||
| MGI | MGI:1933754. Nedd4l. | ||||||||||||||||||||||||
| Rouge | Search... | ||||||||||||||||||||||||
Phylogenomic databases | |||||||||||||||||||||||||
| eggNOG | COG5021. | ||||||||||||||||||||||||
| HOGENOM | HOG000208451. | ||||||||||||||||||||||||
| HOVERGEN | HBG004134. | ||||||||||||||||||||||||
| InParanoid | Q8CFI0. | ||||||||||||||||||||||||
| OrthoDB | EOG4QRH3C. | ||||||||||||||||||||||||
Enzyme and pathway databases | |||||||||||||||||||||||||
| UniPathway | UPA00143. | ||||||||||||||||||||||||
Gene expression databases | |||||||||||||||||||||||||
| Genevestigator | Q8CFI0. | ||||||||||||||||||||||||
| GermOnline | ENSMUSG00000024589. Mus musculus. | ||||||||||||||||||||||||
Family and domain databases | |||||||||||||||||||||||||
| InterPro | IPR000008. C2_Ca-dep. IPR008973. C2_Ca/lipid-bd_dom_CaLB. IPR020477. C2_dom. IPR018029. C2_membr_targeting. IPR024928. E3_ub_ligase_SMURF1. IPR000569. HECT. IPR001202. WW_dom. [Graphical view] | ||||||||||||||||||||||||
| Pfam | PF00168. C2. 1 hit. PF00632. HECT. 1 hit. PF00397. WW. 4 hits. [Graphical view] | ||||||||||||||||||||||||
| PIRSF | PIRSF001569. E3_ub_ligase_SMURF1. 1 hit. | ||||||||||||||||||||||||
| PRINTS | PR00360. C2DOMAIN. | ||||||||||||||||||||||||
| SMART | SM00239. C2. 1 hit. SM00119. HECTc. 1 hit. SM00456. WW. 4 hits. [Graphical view] | ||||||||||||||||||||||||
| SUPFAM | SSF49562. C2_CaLB. 1 hit. SSF56204. HECT. 1 hit. SSF51045. WW_Rsp5_WWP. 4 hits. | ||||||||||||||||||||||||
| PROSITE | PS50004. C2. 1 hit. PS50237. HECT. 1 hit. PS01159. WW_DOMAIN_1. 4 hits. PS50020. WW_DOMAIN_2. 4 hits. [Graphical view] | ||||||||||||||||||||||||
| ProtoNet | Search... | ||||||||||||||||||||||||
Other | |||||||||||||||||||||||||
| ChiTaRS | NEDD4L. mouse. | ||||||||||||||||||||||||
| EvolutionaryTrace | Q8CFI0. | ||||||||||||||||||||||||
| SOURCE | Search... | ||||||||||||||||||||||||
Entry information
| Entry name | NED4L_MOUSE | ||||||||
| Accession | Primary (citable) accession number: Q8CFI0 Secondary accession number(s): Q8BRT9, Q8BS42, Q99PK2 | ||||||||
| Entry history |
| ||||||||
| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation program | Chordata Protein Annotation Program | ||||||||
Relevant documents
| MGD cross-references Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot |
| PATHWAY comments Index of metabolic and biosynthesis pathways |
| PDB cross-references Index of Protein Data Bank (PDB) cross-references |
| SIMILARITY comments Index of protein domains and families |

Clusters with
