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Protein

E3 ubiquitin-protein ligase NEDD4-like

Gene

Nedd4l

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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. 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. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1. Plays a role in dendrite formation by melanocytes (By similarity).By similarity5 Publications

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.

Enzyme regulationi

Activated by NDFIP1- and NDFIP2-binding. Interacts with SGK1.By similarity

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei971Glycyl thioester intermediate1

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Transferase

Keywords - Biological processi

Differentiation, Ubl conjugation pathway

Enzyme and pathway databases

UniPathwayiUPA00143.

Protein family/group databases

TCDBi8.A.30.1.1. the nedd4-family interacting protein-2 (nedd4) family.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase NEDD4-like (EC:2.3.2.26)
Alternative name(s):
HECT-type E3 ubiquitin transferase NED4L
NEDD4.2
Nedd4-2
Gene namesi
Name:Nedd4l
Synonyms:Kiaa0439, Nedd4b
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1933754. Nedd4l.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi371S → A: Weakly reduces phosphorylation by SGK1. 1 Publication1
Mutagenesisi477S → A: Strongly reduces phosphorylation by SGK1. 1 Publication1
Mutagenesisi971C → S: Abolishes catalytic activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001203241 – 1004E3 ubiquitin-protein ligase NEDD4-likeAdd BLAST1004

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei341PhosphoserineBy similarity1
Modified residuei347PhosphothreonineBy similarity1
Modified residuei371Phosphoserine; by WNK1 and WNK41 Publication1
Modified residuei396Phosphothreonine; by SGK1By similarity1
Modified residuei475PhosphoserineBy similarity1
Modified residuei477Phosphoserine; by SGK12 Publications1
Modified residuei478PhosphoserineCombined sources1
Modified residuei493PhosphoserineCombined sources1
Modified residuei504PhosphoserineBy similarity1
Modified residuei508PhosphoserineCombined sources1
Modified residuei512PhosphoserineCombined sources1
Modified residuei516PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated; which impairs interaction with SCNN. Interaction with YWHAH inhibits dephosphorylation (By similarity). Aldosterone induces Ser-477 phosphorylation by SGK1.By similarity2 Publications
Auto-ubiquitinated.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ8CFI0.
PeptideAtlasiQ8CFI0.
PRIDEiQ8CFI0.

PTM databases

iPTMnetiQ8CFI0.
PhosphoSitePlusiQ8CFI0.

Expressioni

Tissue specificityi

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.2 Publications

Interactioni

Subunit structurei

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. Interacts with ARRDC4 (By similarity). Interacts with KCNQ1; promotes internalization of KCNQ1 (By similarity).By similarity6 Publications

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-48843N.
IntActiQ8CFI0. 2 interactors.
MINTiMINT-5097552.
STRINGi10090.ENSMUSP00000132838.

Structurei

Secondary structure

11004
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi227 – 231Combined sources5
Beta strandi233 – 235Combined sources3
Beta strandi237 – 241Combined sources5
Turni242 – 244Combined sources3
Beta strandi247 – 250Combined sources4
Beta strandi420 – 424Combined sources5
Beta strandi426 – 428Combined sources3
Beta strandi430 – 434Combined sources5
Turni435 – 438Combined sources4
Beta strandi439 – 443Combined sources5
Beta strandi532 – 536Combined sources5
Beta strandi542 – 546Combined sources5
Turni547 – 550Combined sources4
Beta strandi551 – 555Combined sources5
Helixi557 – 559Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1WR3NMR-A221-254[»]
1WR4NMR-A414-447[»]
1WR7NMR-A525-560[»]
ProteinModelPortaliQ8CFI0.
SMRiQ8CFI0.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ8CFI0.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini35 – 137C2PROSITE-ProRule annotationAdd BLAST103
Domaini221 – 254WW 1PROSITE-ProRule annotationAdd BLAST34
Domaini414 – 447WW 2PROSITE-ProRule annotationAdd BLAST34
Domaini526 – 559WW 3PROSITE-ProRule annotationAdd BLAST34
Domaini577 – 610WW 4PROSITE-ProRule annotationAdd BLAST34
Domaini669 – 1003HECTPROSITE-ProRule annotationAdd BLAST335

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi321 – 324Poly-Pro4

Sequence similaritiesi

Contains 1 C2 domain.PROSITE-ProRule annotation
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

eggNOGiKOG0940. Eukaryota.
COG5021. LUCA.
HOGENOMiHOG000208451.
HOVERGENiHBG004134.
InParanoidiQ8CFI0.
PhylomeDBiQ8CFI0.

Family and domain databases

CDDicd00078. HECTc. 1 hit.
Gene3Di2.60.40.150. 1 hit.
InterProiIPR000008. C2_dom.
IPR000569. HECT_dom.
IPR001202. WW_dom.
[Graphical view]
PfamiPF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 4 hits.
[Graphical view]
PRINTSiPR00360. C2DOMAIN.
SMARTiSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 4 hits.
[Graphical view]
SUPFAMiSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 4 hits.
SSF56204. SSF56204. 1 hit.
PROSITEiPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 4 hits.
PS50020. WW_DOMAIN_2. 4 hits.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8CFI0-1) [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

        10         20         30         40         50
MSLCEAPVHV GDKELKYFQI PQMLSQLSLL ASHHSRGLEF SGGQGESRIL
60 70 80 90 100
RVKVVSGIDL AKKDIFGASD PYVKLSLYVA DENRELALVQ TKTIKKTLNP
110 120 130 140 150
KWNEEFYFRV NPSNHRLLFE VFDENRLTRD DFLGQVDVPL SHLPTEDPTM
160 170 180 190 200
ERPYTFKDFL LRPRSHKSRV KGFLRLKMAY MPKNGGQDEE NSEQRDDMEH
210 220 230 240 250
GWEVVDSNDS ASQHQEELPP PPLPPGWEEK VDNLGRTYYV NHNNRSTQWH
260 270 280 290 300
RPSLMDVSSE SDNNIRQINQ EAAHRRFRSR RHISEDLEPE ASEGGGEGPE
310 320 330 340 350
PWETISEEMN MAGDSLSLAL PPPPASPVSR TSPQELSEEV SRRLQITPDS
360 370 380 390 400
NGEQFSSLIQ REPSSRLRSC SVTDTVAEQA HLPPPSTPTR RARSSTVTGG
410 420 430 440 450
EEPTPSVAYV HTTPGLPSGW EERKDAKGRT YYVNHNNRTT TWTRPIMQLA
460 470 480 490 500
EDGASGSATN SNNHLVEPQI RRPRSLSSPT VTLSAPLEGA KDSPIRRAVK
510 520 530 540 550
DTLSNPQSPQ PSPYNSPKPQ HKVTQSFLPP GWEMRIAPNG RPFFIDHNTK
560 570 580 590 600
TTTWEDPRLK FPVHMRSKAS LNPNDLGPLP PGWEERIHLD GRTFYIDHNS
610 620 630 640 650
KITQWEDPRL QNPAITGPAV PYSREFKQKY DYFRKKLKKP ADIPNRFEMK
660 670 680 690 700
LHRNNIFEES YRRIMSVKRP DVLKARLWIE FESEKGLDYG GVAREWFFLL
710 720 730 740 750
SKEMFNPYYG LFEYSATDNY TLQINPNSGL CNEDHLSYFT FIGRVAGLAV
760 770 780 790 800
FHGKLLDGFF IRPFYKMMLG KQITLNDMES VDSEYYNSLK WILENDPTEL
810 820 830 840 850
DLMFCIDEEN FGQTYQVDLK PNGSEIMVTN ENKREYIDLV IQWRFVNRVQ
860 870 880 890 900
KQMNAFLEGF TELLPIDLIK IFDENELELL MCGLGDVDVN DWRQHSIYKN
910 920 930 940 950
GYCPNHPVIQ WFWKAVLLMD AEKRIRLLQF VTGTSRVPMN GFAELYGSNG
960 970 980 990 1000
PQLFTIEQWG SPEKLPRAHT CFNRLDLPPY ETFEDLREKL LMAVENAQGF

EGVD
Length:1,004
Mass (Da):115,419
Last modified:August 30, 2005 - v2
Checksum:i50CBB3436052AA60
GO
Isoform 2 (identifier: Q8CFI0-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-149: Missing.

Show »
Length:855
Mass (Da):98,466
Checksum:i96C452B442855895
GO
Isoform 3 (identifier: Q8CFI0-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     385-404: Missing.

Show »
Length:984
Mass (Da):113,350
Checksum:iB6888DF5810B6362
GO

Sequence cautioni

The sequence BAC31307 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti179A → G in AAK00809 (PubMed:11149908).Curated1
Sequence conflicti390R → G in AAK00809 (PubMed:11149908).Curated1
Sequence conflicti403P → S in AAK00809 (PubMed:11149908).Curated1
Sequence conflicti585E → G in AAK00809 (PubMed:11149908).Curated1
Sequence conflicti832N → T in AAK00809 (PubMed:11149908).Curated1
Sequence conflicti847N → D in AAK00809 (PubMed:11149908).Curated1
Sequence conflicti949N → K in BAC31307 (PubMed:16141072).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0154501 – 149Missing in isoform 2. 2 PublicationsAdd BLAST149
Alternative sequenceiVSP_015453385 – 404Missing in isoform 3. 2 PublicationsAdd BLAST20

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF277232 mRNA. Translation: AAK00809.1.
BC039746 mRNA. Translation: AAH39746.1.
BC071210 mRNA. Translation: AAH71210.1.
AK042621 mRNA. Translation: BAC31307.1. Different initiation.
CCDSiCCDS29305.1. [Q8CFI0-2]
UniGeneiMm.98668.

Genome annotation databases

UCSCiuc008fen.2. mouse. [Q8CFI0-3]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF277232 mRNA. Translation: AAK00809.1.
BC039746 mRNA. Translation: AAH39746.1.
BC071210 mRNA. Translation: AAH71210.1.
AK042621 mRNA. Translation: BAC31307.1. Different initiation.
CCDSiCCDS29305.1. [Q8CFI0-2]
UniGeneiMm.98668.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1WR3NMR-A221-254[»]
1WR4NMR-A414-447[»]
1WR7NMR-A525-560[»]
ProteinModelPortaliQ8CFI0.
SMRiQ8CFI0.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-48843N.
IntActiQ8CFI0. 2 interactors.
MINTiMINT-5097552.
STRINGi10090.ENSMUSP00000132838.

Protein family/group databases

TCDBi8.A.30.1.1. the nedd4-family interacting protein-2 (nedd4) family.

PTM databases

iPTMnetiQ8CFI0.
PhosphoSitePlusiQ8CFI0.

Proteomic databases

PaxDbiQ8CFI0.
PeptideAtlasiQ8CFI0.
PRIDEiQ8CFI0.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

UCSCiuc008fen.2. mouse. [Q8CFI0-3]

Organism-specific databases

MGIiMGI:1933754. Nedd4l.
RougeiSearch...

Phylogenomic databases

eggNOGiKOG0940. Eukaryota.
COG5021. LUCA.
HOGENOMiHOG000208451.
HOVERGENiHBG004134.
InParanoidiQ8CFI0.
PhylomeDBiQ8CFI0.

Enzyme and pathway databases

UniPathwayiUPA00143.

Miscellaneous databases

ChiTaRSiNedd4l. mouse.
EvolutionaryTraceiQ8CFI0.
PROiQ8CFI0.
SOURCEiSearch...

Family and domain databases

CDDicd00078. HECTc. 1 hit.
Gene3Di2.60.40.150. 1 hit.
InterProiIPR000008. C2_dom.
IPR000569. HECT_dom.
IPR001202. WW_dom.
[Graphical view]
PfamiPF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 4 hits.
[Graphical view]
PRINTSiPR00360. C2DOMAIN.
SMARTiSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 4 hits.
[Graphical view]
SUPFAMiSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 4 hits.
SSF56204. SSF56204. 1 hit.
PROSITEiPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 4 hits.
PS50020. WW_DOMAIN_2. 4 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiNED4L_MOUSE
AccessioniPrimary (citable) accession number: Q8CFI0
Secondary accession number(s): Q8BRT9, Q8BS42, Q99PK2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: August 30, 2005
Last modified: November 30, 2016
This is version 140 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.