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Protein

NEDD4-like E3 ubiquitin-protein ligase WWP2

Gene

WWP2

Organism
Homo sapiens (Human)
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. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.2 Publications

Miscellaneous

A cysteine residue is required for ubiquitin-thioester formation.

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.2 Publications

Activity regulationi

Activated by NDFIP1- and NDFIP2-binding.1 Publication

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.2 Publications
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 sitei838Glycyl thioester intermediatePROSITE-ProRule annotation1

GO - Molecular functioni

  • RNA polymerase II transcription factor binding Source: BHF-UCL
  • transcription factor binding Source: UniProtKB
  • ubiquitin protein ligase activity Source: GO_Central
  • ubiquitin-protein transferase activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionTransferase
Biological processHost-virus interaction, Ubl conjugation pathway

Enzyme and pathway databases

BRENDAi2.3.2.B9 2681
ReactomeiR-HSA-8948751 Regulation of PTEN stability and activity
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
SignaLinkiO00308
UniPathwayi
UPA00143

Protein family/group databases

MoonDBiO00308 Predicted

Names & Taxonomyi

Protein namesi
Recommended name:
NEDD4-like E3 ubiquitin-protein ligase WWP2 (EC:2.3.2.262 Publications)
Alternative name(s):
Atrophin-1-interacting protein 2
Short name:
AIP2
HECT-type E3 ubiquitin transferase WWP2
WW domain-containing protein 2
Gene namesi
Name:WWP2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

EuPathDBiHostDB:ENSG00000198373.12
HGNCiHGNC:16804 WWP2
MIMi602308 gene
neXtProtiNX_O00308

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

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi498K → R: Does not affect FBXL15-mediated ubiquitination. 1 Publication1
Mutagenesisi500H → K: Does not affect FBXL15-mediated ubiquitination. 1 Publication1
Mutagenesisi838C → A: Abolishes ubiquitination of POU5F1. 1 Publication1

Organism-specific databases

DisGeNETi11060
OpenTargetsiENSG00000198373
PharmGKBiPA134946925

Polymorphism and mutation databases

BioMutaiWWP2

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001203381 – 870NEDD4-like E3 ubiquitin-protein ligase WWP2Add BLAST870

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei211PhosphoserineCombined sources1

Post-translational modificationi

Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome.2 Publications

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO00308
MaxQBiO00308
PaxDbiO00308
PeptideAtlasiO00308
PRIDEiO00308
ProteomicsDBi47835

PTM databases

iPTMnetiO00308
PhosphoSitePlusiO00308

Expressioni

Tissue specificityi

Detected in heart, throughout the brain, placenta, lung, liver, muscle, kidney and pancreas. Also detected in spleen and peripheral blood leukocytes.2 Publications

Developmental stagei

Highly expressed in undifferentiated embryonic stem cells and expression is reduced after embryoid body (EB) formation. Not detectable at day 13 of EB formation; low levels are again detected at day 18 of EB formation.1 Publication

Gene expression databases

BgeeiENSG00000198373 Expressed in 221 organ(s), highest expression level in tibia
CleanExiHS_WWP2
ExpressionAtlasiO00308 baseline and differential
GenevisibleiO00308 HS

Interactioni

Subunit structurei

Interacts with POU5F1, RBP1, EGR2 and SLC11A2 (By similarity). Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1. Interacts with ERBB4, NDFIP1 AND NDFIP2. Interacts with ARRDC4 (PubMed:23236378). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates ARRDC1 (PubMed:22315426, PubMed:21191027). Interacts (via WW domains) with ARRDC2 and ARRDC3 (PubMed:21191027).By similarity10 Publications
(Microbial infection) Interacts with adenovirus type 2 PIII.1 Publication

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi116244, 191 interactors
IntActiO00308, 78 interactors
MINTiO00308
STRINGi9606.ENSP00000348283

Structurei

Secondary structure

1870
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliO00308
SMRiO00308
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini20 – 100C2PROSITE-ProRule annotationAdd BLAST81
Domaini300 – 333WW 1PROSITE-ProRule annotationAdd BLAST34
Domaini330 – 363WW 2PROSITE-ProRule annotationAdd BLAST34
Domaini405 – 437WW 3PROSITE-ProRule annotationAdd BLAST33
Domaini444 – 477WW 4PROSITE-ProRule annotationAdd BLAST34
Domaini536 – 870HECTPROSITE-ProRule annotationAdd BLAST335

Domaini

The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.By similarity
The WW domains mediate interaction with PPxY motif-containing proteins.2 Publications

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0940 Eukaryota
COG5021 LUCA
GeneTreeiENSGT00760000118966
HOGENOMiHOG000208453
HOVERGENiHBG004134
InParanoidiO00308
KOiK05630
OMAiPGWEIRK
OrthoDBiEOG091G0SS8
PhylomeDBiO00308
TreeFamiTF323658

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
PF00632 HECT, 1 hit
PF00397 WW, 4 hits
PIRSFiPIRSF001569 E3_ub_ligase_SMURF1, 1 hit
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
PS50237 HECT, 1 hit
PS01159 WW_DOMAIN_1, 4 hits
PS50020 WW_DOMAIN_2, 4 hits

Sequences (4+)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 4 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: O00308-1) [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
MASASSSRAG VALPFEKSQL TLKVVSAKPK VHNRQPRINS YVEVAVDGLP
60 70 80 90 100
SETKKTGKRI GSSELLWNEI IILNVTAQSH LDLKVWSCHT LRNELLGTAS
110 120 130 140 150
VNLSNVLKNN GGKMENMQLT LNLQTENKGS VVSGGELTIF LDGPTVDLGN
160 170 180 190 200
VPNGSALTDG SQLPSRDSSG TAVAPENRHQ PPSTNCFGGR SRTHRHSGAS
210 220 230 240 250
ARTTPATGEQ SPGARSRHRQ PVKNSGHSGL ANGTVNDEPT TATDPEEPSV
260 270 280 290 300
VGVTSPPAAP LSVTPNPNTT SLPAPATPAE GEEPSTSGTQ QLPAAAQAPD
310 320 330 340 350
ALPAGWEQRE LPNGRVYYVD HNTKTTTWER PLPPGWEKRT DPRGRFYYVD
360 370 380 390 400
HNTRTTTWQR PTAEYVRNYE QWQSQRNQLQ GAMQHFSQRF LYQSSSASTD
410 420 430 440 450
HDPLGPLPPG WEKRQDNGRV YYVNHNTRTT QWEDPRTQGM IQEPALPPGW
460 470 480 490 500
EMKYTSEGVR YFVDHNTRTT TFKDPRPGFE SGTKQGSPGA YDRSFRWKYH
510 520 530 540 550
QFRFLCHSNA LPSHVKISVS RQTLFEDSFQ QIMNMKPYDL RRRLYIIMRG
560 570 580 590 600
EEGLDYGGIA REWFFLLSHE VLNPMYCLFE YAGKNNYCLQ INPASSINPD
610 620 630 640 650
HLTYFRFIGR FIAMALYHGK FIDTGFTLPF YKRMLNKRPT LKDLESIDPE
660 670 680 690 700
FYNSIVWIKE NNLEECGLEL YFIQDMEILG KVTTHELKEG GESIRVTEEN
710 720 730 740 750
KEEYIMLLTD WRFTRGVEEQ TKAFLDGFNE VAPLEWLRYF DEKELELMLC
760 770 780 790 800
GMQEIDMSDW QKSTIYRHYT KNSKQIQWFW QVVKEMDNEK RIRLLQFVTG
810 820 830 840 850
TCRLPVGGFA ELIGSNGPQK FCIDKVGKET WLPRSHTCFN RLDLPPYKSY
860 870
EQLREKLLYA IEETEGFGQE
Length:870
Mass (Da):98,912
Last modified:June 20, 2003 - v2
Checksum:iFCCD75CBA61F2204
GO
Isoform 2 (identifier: O00308-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-116: Missing.

Note: No experimental confirmation available.
Show »
Length:754
Mass (Da):86,308
Checksum:iEB1D2F174EEE0676
GO
Isoform 3 (identifier: O00308-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-439: Missing.

Note: No experimental confirmation available.
Show »
Length:431
Mass (Da):51,079
Checksum:i31464D3E9B6A8F77
GO
Isoform 4 (identifier: O00308-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     336-870: Missing.

Note: No experimental confirmation available.
Show »
Length:335
Mass (Da):35,248
Checksum:i4FDE005EDF329841
GO

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H3BS79H3BS79_HUMAN
NEDD4-like E3 ubiquitin-protein lig...
WWP2
116Annotation score:
H3BRX8H3BRX8_HUMAN
NEDD4-like E3 ubiquitin-protein lig...
WWP2
107Annotation score:
H3BPJ8H3BPJ8_HUMAN
NEDD4-like E3 ubiquitin-protein lig...
WWP2
61Annotation score:

Sequence cautioni

The sequence BAC86528 differs from that shown. Reason: Frameshift at position 757.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti136E → K in AAC51325 (PubMed:9169421).Curated1
Sequence conflicti390F → L in BAG62027 (PubMed:14702039).Curated1
Sequence conflicti394 – 395SS → FW in AAC51325 (PubMed:9169421).Curated2
Sequence conflicti545Y → F in BAC86528 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0464611 – 439Missing in isoform 3. 1 PublicationAdd BLAST439
Alternative sequenceiVSP_0447061 – 116Missing in isoform 2. 1 PublicationAdd BLAST116
Alternative sequenceiVSP_054711336 – 870Missing in isoform 4. 1 PublicationAdd BLAST535

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U96114 mRNA Translation: AAC51325.1
JN712744 mRNA Translation: AFK29253.1
AK126332 mRNA Translation: BAC86528.1 Frameshift.
AK300266 mRNA Translation: BAG62027.1
AK312792 mRNA Translation: BAG35653.1
AC026468 Genomic DNA No translation available.
AC092115 Genomic DNA No translation available.
CH471092 Genomic DNA Translation: EAW83287.1
BC000108 mRNA Translation: AAH00108.1
BC013645 mRNA Translation: AAH13645.1
BC064531 mRNA Translation: AAH64531.1
CCDSiCCDS10885.1 [O00308-1]
CCDS58475.1 [O00308-4]
CCDS58476.1 [O00308-2]
CCDS58477.1 [O00308-3]
RefSeqiNP_001257382.1, NM_001270453.1 [O00308-2]
NP_001257383.1, NM_001270454.1 [O00308-1]
NP_001257384.1, NM_001270455.1 [O00308-4]
NP_008945.2, NM_007014.4 [O00308-1]
NP_955456.1, NM_199424.2 [O00308-3]
XP_011521125.1, XM_011522823.2 [O00308-1]
XP_011521127.1, XM_011522825.1 [O00308-1]
XP_011521128.1, XM_011522826.2 [O00308-2]
XP_016878368.1, XM_017022879.1 [O00308-1]
XP_016878369.1, XM_017022880.1 [O00308-1]
XP_016878370.1, XM_017022881.1 [O00308-1]
UniGeneiHs.408458

Genome annotation databases

EnsembliENST00000356003; ENSP00000348283; ENSG00000198373 [O00308-2]
ENST00000359154; ENSP00000352069; ENSG00000198373 [O00308-1]
ENST00000568684; ENSP00000456216; ENSG00000198373 [O00308-3]
ENST00000569174; ENSP00000455311; ENSG00000198373 [O00308-4]
GeneIDi11060
KEGGihsa:11060
UCSCiuc002exv.3 human [O00308-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U96114 mRNA Translation: AAC51325.1
JN712744 mRNA Translation: AFK29253.1
AK126332 mRNA Translation: BAC86528.1 Frameshift.
AK300266 mRNA Translation: BAG62027.1
AK312792 mRNA Translation: BAG35653.1
AC026468 Genomic DNA No translation available.
AC092115 Genomic DNA No translation available.
CH471092 Genomic DNA Translation: EAW83287.1
BC000108 mRNA Translation: AAH00108.1
BC013645 mRNA Translation: AAH13645.1
BC064531 mRNA Translation: AAH64531.1
CCDSiCCDS10885.1 [O00308-1]
CCDS58475.1 [O00308-4]
CCDS58476.1 [O00308-2]
CCDS58477.1 [O00308-3]
RefSeqiNP_001257382.1, NM_001270453.1 [O00308-2]
NP_001257383.1, NM_001270454.1 [O00308-1]
NP_001257384.1, NM_001270455.1 [O00308-4]
NP_008945.2, NM_007014.4 [O00308-1]
NP_955456.1, NM_199424.2 [O00308-3]
XP_011521125.1, XM_011522823.2 [O00308-1]
XP_011521127.1, XM_011522825.1 [O00308-1]
XP_011521128.1, XM_011522826.2 [O00308-2]
XP_016878368.1, XM_017022879.1 [O00308-1]
XP_016878369.1, XM_017022880.1 [O00308-1]
XP_016878370.1, XM_017022881.1 [O00308-1]
UniGeneiHs.408458

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4Y07X-ray2.51A492-865[»]
5TJ7X-ray2.60A/B/C/D334-865[»]
5TJ8X-ray2.30A334-865[»]
5TJQX-ray2.75A334-865[»]
ProteinModelPortaliO00308
SMRiO00308
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116244, 191 interactors
IntActiO00308, 78 interactors
MINTiO00308
STRINGi9606.ENSP00000348283

Protein family/group databases

MoonDBiO00308 Predicted

PTM databases

iPTMnetiO00308
PhosphoSitePlusiO00308

Polymorphism and mutation databases

BioMutaiWWP2

Proteomic databases

EPDiO00308
MaxQBiO00308
PaxDbiO00308
PeptideAtlasiO00308
PRIDEiO00308
ProteomicsDBi47835

Protocols and materials databases

DNASUi11060
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000356003; ENSP00000348283; ENSG00000198373 [O00308-2]
ENST00000359154; ENSP00000352069; ENSG00000198373 [O00308-1]
ENST00000568684; ENSP00000456216; ENSG00000198373 [O00308-3]
ENST00000569174; ENSP00000455311; ENSG00000198373 [O00308-4]
GeneIDi11060
KEGGihsa:11060
UCSCiuc002exv.3 human [O00308-1]

Organism-specific databases

CTDi11060
DisGeNETi11060
EuPathDBiHostDB:ENSG00000198373.12
GeneCardsiWWP2
HGNCiHGNC:16804 WWP2
MIMi602308 gene
neXtProtiNX_O00308
OpenTargetsiENSG00000198373
PharmGKBiPA134946925
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0940 Eukaryota
COG5021 LUCA
GeneTreeiENSGT00760000118966
HOGENOMiHOG000208453
HOVERGENiHBG004134
InParanoidiO00308
KOiK05630
OMAiPGWEIRK
OrthoDBiEOG091G0SS8
PhylomeDBiO00308
TreeFamiTF323658

Enzyme and pathway databases

UniPathwayi
UPA00143

BRENDAi2.3.2.B9 2681
ReactomeiR-HSA-8948751 Regulation of PTEN stability and activity
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
SignaLinkiO00308

Miscellaneous databases

ChiTaRSiWWP2 human
GeneWikiiWWP2
GenomeRNAii11060
PROiPR:O00308
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000198373 Expressed in 221 organ(s), highest expression level in tibia
CleanExiHS_WWP2
ExpressionAtlasiO00308 baseline and differential
GenevisibleiO00308 HS

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
PF00632 HECT, 1 hit
PF00397 WW, 4 hits
PIRSFiPIRSF001569 E3_ub_ligase_SMURF1, 1 hit
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
PS50237 HECT, 1 hit
PS01159 WW_DOMAIN_1, 4 hits
PS50020 WW_DOMAIN_2, 4 hits
ProtoNetiSearch...

Entry informationi

Entry nameiWWP2_HUMAN
AccessioniPrimary (citable) accession number: O00308
Secondary accession number(s): A6NEP1
, B2R706, B4DTL5, F5H213, H3BRF3, I3RSG8, Q6ZTQ5, Q96CZ2, Q9BWN6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 20, 2003
Last sequence update: June 20, 2003
Last modified: November 7, 2018
This is version 182 of the entry and version 2 of the sequence. See 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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 16
    Human chromosome 16: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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