Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

E3 ubiquitin-protein ligase NEDD4-like

Gene

Nedd4l

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 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). Involved in the regulation of TOR signaling (By similarity). Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF (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 + N6-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

Keywordsi

Molecular functionTransferase
Biological processDifferentiation, 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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1933754 Nedd4l

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Endosome, Golgi apparatus

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. Deubiquitinated by USP36, no effect on NEDD4L protein levels. Both proteins interact and regulate each other's ubiquitination levels.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

Developmental stagei

In the developing brain, it is homogenously distributed in the cortical plate, ventricular zone and ganglionic eminences at E15. A peak of expression in the cortex is observed at E16.5.1 Publication

Interactioni

Subunit structurei

Interacts with SMAD2, SMAD3, SMAD6 and SMAD7 (By similarity). Interacts with CLCN5 (By similarity). The phosphorylated form interacts with 14-3-3 proteins (By similarity). Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A and SCN10A (PubMed:11244092., PubMed:11742982, PubMed:12424229, PubMed:15123669). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase (PubMed:12050153). Interacts with TNK2 (By similarity). Interacts (via C2 domain) with NPC2 (By similarity). Interacts with ARRDC4 (By similarity). Interacts with KCNQ1; promotes internalization of KCNQ1 (By similarity). Interacts (via domains WW1, 3 and 4) with USP36; the interaction inhibits ubiquitination of, at least, NTRK1, KCNQ2 and KCNQ3 by NEDD4L (By similarity).By similarity6 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

DIPiDIP-48843N
IntActiQ8CFI0, 10 interactors
MINTiQ8CFI0
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

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0940 Eukaryota
COG5021 LUCA
HOGENOMiHOG000208451
HOVERGENiHBG004134
InParanoidiQ8CFI0
PhylomeDBiQ8CFI0

Family and domain databases

CDDicd00078 HECTc, 1 hit
cd00201 WW, 4 hits
Gene3Di2.60.40.150, 1 hit
InterProiView protein in InterPro
IPR000008 C2_dom
IPR035892 C2_domain_sf
IPR024928 E3_ub_ligase_SMURF1
IPR000569 HECT_dom
IPR035983 Hect_E3_ubiquitin_ligase
IPR001202 WW_dom
IPR036020 WW_dom_sf
PfamiView protein in Pfam
PF00168 C2, 1 hit
PF00632 HECT, 1 hit
PF00397 WW, 4 hits
PIRSFiPIRSF001569 E3_ub_ligase_SMURF1, 1 hit
PRINTSiPR00360 C2DOMAIN
SMARTiView protein in SMART
SM00239 C2, 1 hit
SM00119 HECTc, 1 hit
SM00456 WW, 4 hits
SUPFAMiSSF51045 SSF51045, 4 hits
SSF56204 SSF56204, 1 hit
PROSITEiView protein in PROSITE
PS50004 C2, 1 hit
PS50237 HECT, 1 hit
PS01159 WW_DOMAIN_1, 4 hits
PS50020 WW_DOMAIN_2, 4 hits

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. Translation N-terminally extended.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

Similar proteinsi

Entry informationi

Entry nameiNED4L_MOUSE
AccessioniPrimary (citable) accession number: Q8CFI0
Secondary accession number(s): Q8BRT9, Q8BS42, Q99PK2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: August 30, 2005
Last modified: May 23, 2018
This is version 152 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Cookie policy

We would like to use anonymized google analytics cookies to gather statistics on how uniprot.org is used in aggregate. Learn more

UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health