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Protein

E3 ubiquitin-protein ligase SMURF2

Gene

SMURF2

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. Interacts with SMAD1 and SMAD7 in order to trigger their ubiquitination and proteasome-dependent degradation. In addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with SCYE1. Forms a stable complex with the TGF-beta receptor-mediated phosphorylated SMAD2 and SMAD3. In this way, SMAD2 may recruit substrates, such as SNON, for ubiquitin-mediated degradation. Enhances the inhibitory activity of SMAD7 and reduces the transcriptional activity of SMAD2. Coexpression of SMURF2 with SMAD1 results in considerable decrease in steady-state level of SMAD1 protein and a smaller decrease of SMAD2 level.2 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.By similarity

Enzyme regulationi

Activated by NDFIP1- and NDFIP2-binding.

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 sitei716Glycyl thioester intermediatePROSITE-ProRule annotation1

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • SMAD binding Source: BHF-UCL
  • transforming growth factor beta receptor binding Source: Ensembl
  • ubiquitin protein ligase activity Source: GO_Central
  • ubiquitin-protein transferase activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionTransferase
Biological processUbl conjugation pathway

Enzyme and pathway databases

BRENDAi6.3.2.19 2681
ReactomeiR-HSA-201451 Signaling by BMP
R-HSA-2173788 Downregulation of TGF-beta receptor signaling
R-HSA-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-4608870 Asymmetric localization of PCP proteins
R-HSA-4641257 Degradation of AXIN
R-HSA-5632684 Hedgehog 'on' state
R-HSA-5689880 Ub-specific processing proteases
R-HSA-8941858 Regulation of RUNX3 expression and activity
R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation
SignaLinkiQ9HAU4
SIGNORiQ9HAU4
UniPathwayiUPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase SMURF2 (EC:2.3.2.26By similarity)
Short name:
hSMURF2
Alternative name(s):
HECT-type E3 ubiquitin transferase SMURF2
SMAD ubiquitination regulatory factor 2
SMAD-specific E3 ubiquitin-protein ligase 2
Gene namesi
Name:SMURF2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000108854.15
HGNCiHGNC:16809 SMURF2
MIMi605532 gene
neXtProtiNX_Q9HAU4

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

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi29F → A: Increases autoubiquitination; when associated with A-30. 1 Publication1
Mutagenesisi30F → A: Increases autoubiquitination; when associated with A-29. 1 Publication1
Mutagenesisi56T → A: Increases autoubiquitination; when associated with A-57. 1 Publication1
Mutagenesisi57L → A: Increases autoubiquitination; when associated with A-56. 1 Publication1
Mutagenesisi251 – 284Missing : Abolishes interaction with SMAD2 and SMAD7. 2 PublicationsAdd BLAST34
Mutagenesisi297 – 330Missing : Abolishes interaction with SMAD7. 1 PublicationAdd BLAST34
Mutagenesisi535W → A: Loss of catalytic activity. 1 Publication1
Mutagenesisi535W → D: Loss of catalytic activity. 1 Publication1
Mutagenesisi547H → A: Partial loss of catalytic activity. 1 Publication1
Mutagenesisi547H → F or I: Activates autocatalytic activity. 1 Publication1
Mutagenesisi581Y → A: Loss of catalytic activity. 1 Publication1
Mutagenesisi716C → A: Increases Smad7-bound TGF-beta receptors in membrane rafts. 3 Publications1
Mutagenesisi716C → G: Loss of activity. Loss of ability to ubiquitinate SMAD1 and SMAD2 and no down-regulation of SMAD1 and SMAD2 protein levels. 3 Publications1

Organism-specific databases

DisGeNETi64750
OpenTargetsiENSG00000108854
PharmGKBiPA134985524

Polymorphism and mutation databases

BioMutaiSMURF2
DMDMi17865624

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001203291 – 748E3 ubiquitin-protein ligase SMURF2Add BLAST748

Post-translational modificationi

Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome.2 Publications

Keywords - PTMi

Ubl conjugation

Proteomic databases

EPDiQ9HAU4
MaxQBiQ9HAU4
PaxDbiQ9HAU4
PeptideAtlasiQ9HAU4
PRIDEiQ9HAU4

PTM databases

iPTMnetiQ9HAU4
PhosphoSitePlusiQ9HAU4

Expressioni

Tissue specificityi

Widely expressed.

Gene expression databases

BgeeiENSG00000108854
CleanExiHS_SMURF2
ExpressionAtlasiQ9HAU4 baseline and differential
GenevisibleiQ9HAU4 HS

Organism-specific databases

HPAiHPA071508

Interactioni

Subunit structurei

Interacts (via WW domains) with SMAD1. Interacts (via WW domains) with SMAD2 (via PY-motif). Interacts (via WW domains) with SMAD3 (via PY-motif). Interacts with SMAD6. Interacts with SMAD7 (via PY-motif) and TGFBR1; SMAD7 recruits SMURF2 to the TGF-beta receptor and regulates its degradation. Does not interact with SMAD4; SMAD4 lacks a PY-motif. Interacts with AIMP1. Interacts with STAMBP and RNF11. Interacts with NDFIP1 and NDFIP2 (Probable); this interaction activates the E3 ubiquitin-protein ligase.7 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • SMAD binding Source: BHF-UCL
  • transforming growth factor beta receptor binding Source: Ensembl

Protein-protein interaction databases

BioGridi122265, 132 interactors
CORUMiQ9HAU4
DIPiDIP-33061N
IntActiQ9HAU4, 76 interactors
MINTiQ9HAU4
STRINGi9606.ENSP00000262435

Structurei

Secondary structure

1748
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi12 – 23Combined sources12
Beta strandi35 – 41Combined sources7
Turni42 – 44Combined sources3
Beta strandi48 – 50Combined sources3
Beta strandi60 – 69Combined sources10
Beta strandi75 – 81Combined sources7
Helixi82 – 87Combined sources6
Beta strandi93 – 99Combined sources7
Helixi101 – 110Combined sources10
Beta strandi113 – 115Combined sources3
Beta strandi131 – 138Combined sources8
Beta strandi258 – 262Combined sources5
Turni263 – 265Combined sources3
Beta strandi266 – 271Combined sources6
Turni272 – 275Combined sources4
Beta strandi276 – 280Combined sources5
Beta strandi282 – 284Combined sources3
Beta strandi286 – 288Combined sources3
Helixi293 – 295Combined sources3
Beta strandi301 – 307Combined sources7
Beta strandi309 – 311Combined sources3
Beta strandi313 – 317Combined sources5
Turni318 – 321Combined sources4
Beta strandi322 – 326Combined sources5
Turni328 – 330Combined sources3
Helixi372 – 386Combined sources15
Beta strandi392 – 397Combined sources6
Helixi402 – 411Combined sources10
Helixi415 – 419Combined sources5
Beta strandi420 – 426Combined sources7
Helixi434 – 449Combined sources16
Helixi452 – 454Combined sources3
Beta strandi455 – 460Combined sources6
Beta strandi463 – 469Combined sources7
Helixi473 – 475Combined sources3
Helixi479 – 495Combined sources17
Helixi506 – 512Combined sources7
Helixi522 – 525Combined sources4
Helixi527 – 538Combined sources12
Turni542 – 544Combined sources3
Beta strandi549 – 555Combined sources7
Beta strandi558 – 565Combined sources8
Turni574 – 577Combined sources4
Helixi578 – 590Combined sources13
Turni591 – 594Combined sources4
Helixi595 – 608Combined sources14
Helixi611 – 614Combined sources4
Helixi619 – 627Combined sources9
Beta strandi629 – 631Combined sources3
Helixi634 – 639Combined sources6
Beta strandi641 – 646Combined sources6
Helixi651 – 662Combined sources12
Helixi665 – 676Combined sources12
Beta strandi679 – 681Combined sources3
Helixi686 – 688Combined sources3
Beta strandi698 – 702Combined sources5
Beta strandi712 – 714Combined sources3
Helixi715 – 717Combined sources3
Beta strandi719 – 722Combined sources4
Helixi728 – 739Combined sources12

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1ZVDX-ray2.10A369-748[»]
2DJYNMR-A297-333[»]
2JQZNMR-A10-140[»]
2KXQNMR-A250-333[»]
2LTZNMR-A297-333[»]
ProteinModelPortaliQ9HAU4
SMRiQ9HAU4
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9HAU4

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini1 – 98C2PROSITE-ProRule annotationAdd BLAST98
Domaini157 – 190WW 1PROSITE-ProRule annotationAdd BLAST34
Domaini251 – 284WW 2PROSITE-ProRule annotationAdd BLAST34
Domaini297 – 330WW 3PROSITE-ProRule annotationAdd BLAST34
Domaini414 – 748HECTPROSITE-ProRule annotationAdd BLAST335

Domaini

The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3).
The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain.

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0940 Eukaryota
COG5021 LUCA
GeneTreeiENSGT00760000118966
HOGENOMiHOG000208451
HOVERGENiHBG004134
InParanoidiQ9HAU4
KOiK04678
OMAiSCLVDEN
OrthoDBiEOG091G011S
PhylomeDBiQ9HAU4
TreeFamiTF323658

Family and domain databases

CDDicd00078 HECTc, 1 hit
cd00201 WW, 3 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, 3 hits
PIRSFiPIRSF001569 E3_ub_ligase_SMURF1, 1 hit
SMARTiView protein in SMART
SM00239 C2, 1 hit
SM00119 HECTc, 1 hit
SM00456 WW, 3 hits
SUPFAMiSSF51045 SSF51045, 3 hits
SSF56204 SSF56204, 1 hit
PROSITEiView protein in PROSITE
PS50004 C2, 1 hit
PS50237 HECT, 1 hit
PS01159 WW_DOMAIN_1, 1 hit
PS50020 WW_DOMAIN_2, 3 hits

Sequencei

Sequence statusi: Complete.

Q9HAU4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSNPGGRRNG PVKLRLTVLC AKNLVKKDFF RLPDPFAKVV VDGSGQCHST
60 70 80 90 100
DTVKNTLDPK WNQHYDLYIG KSDSVTISVW NHKKIHKKQG AGFLGCVRLL
110 120 130 140 150
SNAINRLKDT GYQRLDLCKL GPNDNDTVRG QIVVSLQSRD RIGTGGQVVD
160 170 180 190 200
CSRLFDNDLP DGWEERRTAS GRIQYLNHIT RTTQWERPTR PASEYSSPGR
210 220 230 240 250
PLSCFVDENT PISGTNGATC GQSSDPRLAE RRVRSQRHRN YMSRTHLHTP
260 270 280 290 300
PDLPEGYEQR TTQQGQVYFL HTQTGVSTWH DPRVPRDLSN INCEELGPLP
310 320 330 340 350
PGWEIRNTAT GRVYFVDHNN RTTQFTDPRL SANLHLVLNR QNQLKDQQQQ
360 370 380 390 400
QVVSLCPDDT ECLTVPRYKR DLVQKLKILR QELSQQQPQA GHCRIEVSRE
410 420 430 440 450
EIFEESYRQV MKMRPKDLWK RLMIKFRGEE GLDYGGVARE WLYLLSHEML
460 470 480 490 500
NPYYGLFQYS RDDIYTLQIN PDSAVNPEHL SYFHFVGRIM GMAVFHGHYI
510 520 530 540 550
DGGFTLPFYK QLLGKSITLD DMELVDPDLH NSLVWILEND ITGVLDHTFC
560 570 580 590 600
VEHNAYGEII QHELKPNGKS IPVNEENKKE YVRLYVNWRF LRGIEAQFLA
610 620 630 640 650
LQKGFNEVIP QHLLKTFDEK ELELIICGLG KIDVNDWKVN TRLKHCTPDS
660 670 680 690 700
NIVKWFWKAV EFFDEERRAR LLQFVTGSSR VPLQGFKALQ GAAGPRLFTI
710 720 730 740
HQIDACTNNL PKAHTCFNRI DIPPYESYEK LYEKLLTAIE ETCGFAVE
Length:748
Mass (Da):86,196
Last modified:March 1, 2001 - v1
Checksum:i3042B443A3755762
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti6G → R in AAG45422 (PubMed:11016919).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF310676 mRNA Translation: AAG45422.1
AF301463 mRNA Translation: AAG25641.1
AY014180 mRNA Translation: AAG50421.1
BC093876 mRNA Translation: AAH93876.1
BC111945 mRNA Translation: AAI11946.1
CCDSiCCDS32707.1
RefSeqiNP_073576.1, NM_022739.3
UniGeneiHs.515011

Genome annotation databases

EnsembliENST00000262435; ENSP00000262435; ENSG00000108854
GeneIDi64750
KEGGihsa:64750
UCSCiuc002jep.2 human

Similar proteinsi

Entry informationi

Entry nameiSMUF2_HUMAN
AccessioniPrimary (citable) accession number: Q9HAU4
Secondary accession number(s): Q52LL1, Q9H260
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 13, 2001
Last sequence update: March 1, 2001
Last modified: April 25, 2018
This is version 177 of the entry and version 1 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
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Main funding by: National Institutes of Health