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Q8CFI0 (NED4L_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 117. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase NEDD4-like

EC=6.3.2.-
Alternative name(s):
NEDD4.2
Nedd4-2
Gene names
Name:Nedd4l
Synonyms:Kiaa0439, Nedd4b
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1004 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. 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

Protein modification; protein ubiquitination.

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

Cytoplasm Ref.7.

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

Keywords
   Biological processUbl conjugation pathway
   Cellular componentCytoplasm
   Coding sequence diversityAlternative splicing
   DomainRepeat
   Molecular functionLigase
   PTMPhosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processnegative regulation of sodium ion transport

Inferred from direct assay Ref.1PubMed 17715136. Source: MGI

negative regulation of systemic arterial blood pressure

Inferred from mutant phenotype PubMed 18524855. Source: MGI

positive regulation of cation channel activity

Inferred from genetic interaction PubMed 18981174. Source: MGI

positive regulation of sodium ion transport

Inferred from genetic interaction PubMed 18981174. Source: MGI

protein ubiquitination involved in ubiquitin-dependent protein catabolic process

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of tight junction assembly

Inferred from direct assay PubMed 20504882. Source: MGI

response to salt stress

Inferred from mutant phenotype PubMed 18524855. Source: MGI

ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

Inferred from direct assay PubMed 22019085. Source: MGI

   Cellular_componentcytoplasm

Inferred from Biological aspect of Ancestor. Source: RefGenome

nucleus

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Molecular_functionprotein binding

Inferred from physical interaction PubMed 17544362. Source: MGI

sodium channel inhibitor activity

Inferred from direct assay Ref.1. Source: MGI

ubiquitin-protein transferase activity

Inferred from direct assay PubMed 20504882. Source: MGI

Complete GO annotation...

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 10041004E3 ubiquitin-protein ligase NEDD4-like
PRO_0000120324

Regions

Domain35 – 137103C2
Domain221 – 25434WW 1
Domain414 – 44734WW 2
Domain526 – 55934WW 3
Domain577 – 61034WW 4
Domain669 – 1003335HECT
Compositional bias321 – 3244Poly-Pro

Sites

Active site9711Glycyl thioester intermediate

Amino acid modifications

Modified residue3471Phosphothreonine By similarity
Modified residue3711Phosphoserine; by WNK1 and WNK4 Ref.5
Modified residue3961Phosphothreonine; by SGK1 By similarity
Modified residue4751Phosphoserine By similarity
Modified residue4771Phosphoserine; by SGK1 Ref.5 Ref.10
Modified residue4781Phosphoserine; by WNK1 and WNK4 By similarity
Modified residue4931Phosphoserine By similarity
Modified residue5081Phosphoserine Ref.11
Modified residue5121Phosphoserine By similarity
Modified residue5161Phosphoserine By similarity

Natural variations

Alternative sequence1 – 149149Missing in isoform 2.
VSP_015450
Alternative sequence385 – 40420Missing in isoform 3.
VSP_015453

Experimental info

Mutagenesis3711S → A: Weakly reduces phosphorylation by SGK1. Ref.5
Mutagenesis4771S → A: Strongly reduces phosphorylation by SGK1. Ref.5
Mutagenesis9711C → S: Abolishes catalytic activity. Ref.1
Sequence conflict1791A → G in AAK00809. Ref.1
Sequence conflict3901R → G in AAK00809. Ref.1
Sequence conflict4031P → S in AAK00809. Ref.1
Sequence conflict5851E → G in AAK00809. Ref.1
Sequence conflict8321N → T in AAK00809. Ref.1
Sequence conflict8471N → D in AAK00809. Ref.1
Sequence conflict9491N → K in BAC31307. Ref.4

Secondary structure

.......................... 1004
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified August 30, 2005. Version 2.
Checksum: 50CBB3436052AA60

FASTA1,004115,419
        10         20         30         40         50         60 
MSLCEAPVHV GDKELKYFQI PQMLSQLSLL ASHHSRGLEF SGGQGESRIL RVKVVSGIDL 

        70         80         90        100        110        120 
AKKDIFGASD PYVKLSLYVA DENRELALVQ TKTIKKTLNP KWNEEFYFRV NPSNHRLLFE 

       130        140        150        160        170        180 
VFDENRLTRD DFLGQVDVPL SHLPTEDPTM ERPYTFKDFL LRPRSHKSRV KGFLRLKMAY 

       190        200        210        220        230        240 
MPKNGGQDEE NSEQRDDMEH GWEVVDSNDS ASQHQEELPP PPLPPGWEEK VDNLGRTYYV 

       250        260        270        280        290        300 
NHNNRSTQWH RPSLMDVSSE SDNNIRQINQ EAAHRRFRSR RHISEDLEPE ASEGGGEGPE 

       310        320        330        340        350        360 
PWETISEEMN MAGDSLSLAL PPPPASPVSR TSPQELSEEV SRRLQITPDS NGEQFSSLIQ 

       370        380        390        400        410        420 
REPSSRLRSC SVTDTVAEQA HLPPPSTPTR RARSSTVTGG EEPTPSVAYV HTTPGLPSGW 

       430        440        450        460        470        480 
EERKDAKGRT YYVNHNNRTT TWTRPIMQLA EDGASGSATN SNNHLVEPQI RRPRSLSSPT 

       490        500        510        520        530        540 
VTLSAPLEGA KDSPIRRAVK DTLSNPQSPQ PSPYNSPKPQ HKVTQSFLPP GWEMRIAPNG 

       550        560        570        580        590        600 
RPFFIDHNTK TTTWEDPRLK FPVHMRSKAS LNPNDLGPLP PGWEERIHLD GRTFYIDHNS 

       610        620        630        640        650        660 
KITQWEDPRL QNPAITGPAV PYSREFKQKY DYFRKKLKKP ADIPNRFEMK LHRNNIFEES 

       670        680        690        700        710        720 
YRRIMSVKRP DVLKARLWIE FESEKGLDYG GVAREWFFLL SKEMFNPYYG LFEYSATDNY 

       730        740        750        760        770        780 
TLQINPNSGL CNEDHLSYFT FIGRVAGLAV FHGKLLDGFF IRPFYKMMLG KQITLNDMES 

       790        800        810        820        830        840 
VDSEYYNSLK WILENDPTEL DLMFCIDEEN FGQTYQVDLK PNGSEIMVTN ENKREYIDLV 

       850        860        870        880        890        900 
IQWRFVNRVQ KQMNAFLEGF TELLPIDLIK IFDENELELL MCGLGDVDVN DWRQHSIYKN 

       910        920        930        940        950        960 
GYCPNHPVIQ WFWKAVLLMD AEKRIRLLQF VTGTSRVPMN GFAELYGSNG PQLFTIEQWG 

       970        980        990       1000 
SPEKLPRAHT CFNRLDLPPY ETFEDLREKL LMAVENAQGF EGVD 

« Hide

Isoform 2 [UniParc].

Checksum: 96C452B442855895
Show »

FASTA85598,466
Isoform 3 [UniParc].

Checksum: B6888DF5810B6362
Show »

FASTA984113,350

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. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai 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]"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 SER-508, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
[12]"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.
CCDSCCDS29305.1. [Q8CFI0-2]
UniGeneMm.98668.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1WR3NMR-A221-254[»]
1WR4NMR-A414-447[»]
1WR7NMR-A525-560[»]
ProteinModelPortalQ8CFI0.
SMRQ8CFI0. Positions 40-182, 221-254, 415-449, 525-560, 569-617, 623-995.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-48843N.
IntActQ8CFI0. 2 interactions.
MINTMINT-5097552.

Protein family/group databases

TCDB8.A.30.1.1. the nedd4-family interacting protein-2 (nedd4) family.

PTM databases

PhosphoSiteQ8CFI0.

Proteomic databases

MaxQBQ8CFI0.
PaxDbQ8CFI0.
PRIDEQ8CFI0.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Organism-specific databases

MGIMGI:1933754. Nedd4l.
RougeSearch...

Phylogenomic databases

eggNOGCOG5021.
HOGENOMHOG000208451.
HOVERGENHBG004134.
InParanoidQ8CFI0.
PhylomeDBQ8CFI0.

Enzyme and pathway databases

UniPathwayUPA00143.

Gene expression databases

GenevestigatorQ8CFI0.

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. 4 hits.
[Graphical view]
PIRSFPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
PRINTSPR00360. C2DOMAIN.
SMARTSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 4 hits.
[Graphical view]
SUPFAMSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 4 hits.
SSF56204. SSF56204. 1 hit.
PROSITEPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 4 hits.
PS50020. WW_DOMAIN_2. 4 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSNEDD4L. mouse.
EvolutionaryTraceQ8CFI0.
PROQ8CFI0.
SOURCESearch...

Entry information

Entry nameNED4L_MOUSE
AccessionPrimary (citable) accession number: Q8CFI0
Secondary accession number(s): Q8BRT9, Q8BS42, Q99PK2
Entry history
Integrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: August 30, 2005
Last modified: July 9, 2014
This is version 117 of the entry and version 2 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

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot