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Q9HAU4 (SMUF2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 137. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase SMURF2

Short name=hSMURF2
EC=6.3.2.-
Alternative name(s):
SMAD ubiquitination regulatory factor 2
SMAD-specific E3 ubiquitin-protein ligase 2
Gene names
Name:SMURF2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length748 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. 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. Ref.5 Ref.6

Enzyme regulation

Activated by NDFIP1- and NDFIP2-binding.

Pathway

Protein modification; protein ubiquitination.

Subunit structure

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. Ref.1 Ref.5 Ref.8 Ref.9 Ref.10 Ref.13

Subcellular location

Nucleus. Cytoplasm. Cell membrane. Membrane raft. Note: Cytoplasmic in the presence of SMAD7. Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts. Ref.6

Tissue specificity

Widely expressed.

Domain

The second and third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3). Ref.15

The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain. Ref.15

Post-translational modification

Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and UBE2D1. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome. Ref.11 Ref.12

Sequence similarities

Contains 1 C2 domain.

Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.

Contains 3 WW domains.

Ontologies

Keywords
   Biological processUbl conjugation pathway
   Cellular componentCell membrane
Cytoplasm
Membrane
Nucleus
   DomainRepeat
   Molecular functionLigase
   PTMUbl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processBMP signaling pathway

Traceable author statement. Source: Reactome

gene expression

Traceable author statement. Source: Reactome

negative regulation of transcription from RNA polymerase II promoter

Traceable author statement. Source: Reactome

negative regulation of transcription, DNA-templated

Non-traceable author statement Ref.2. Source: UniProtKB

negative regulation of transforming growth factor beta receptor signaling pathway

Traceable author statement. Source: Reactome

protein ubiquitination involved in ubiquitin-dependent protein catabolic process

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of transforming growth factor beta receptor signaling pathway

Non-traceable author statement Ref.3. Source: UniProtKB

transcription initiation from RNA polymerase II promoter

Traceable author statement. Source: Reactome

transcription, DNA-templated

Traceable author statement. Source: Reactome

transforming growth factor beta receptor signaling pathway

Inferred from Biological aspect of Ancestor. Source: RefGenome

ubiquitin-dependent SMAD protein catabolic process

Inferred from direct assay PubMed 19122240. Source: BHF-UCL

ubiquitin-dependent protein catabolic process

Inferred from direct assay Ref.9. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from Biological aspect of Ancestor. Source: RefGenome

cytosol

Traceable author statement. Source: Reactome

membrane raft

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Non-traceable author statement Ref.1. Source: UniProtKB

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

ubiquitin ligase complex

Inferred from direct assay Ref.9. Source: UniProtKB

   Molecular_functionSMAD binding

Inferred from physical interaction PubMed 19122240. Source: BHF-UCL

identical protein binding

Inferred from physical interaction PubMed 15231748Ref.15. Source: IntAct

ubiquitin-protein ligase activity

Inferred from direct assay Ref.9. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 748748E3 ubiquitin-protein ligase SMURF2
PRO_0000120329

Regions

Domain1 – 9898C2
Domain157 – 19034WW 1
Domain251 – 28434WW 2
Domain297 – 33034WW 3
Domain414 – 748335HECT

Sites

Active site7161Glycyl thioester intermediate By similarity

Experimental info

Mutagenesis291F → A: Increases autoubiquitination; when associated with A-30. Ref.15
Mutagenesis301F → A: Increases autoubiquitination; when associated with A-29. Ref.15
Mutagenesis561T → A: Increases autoubiquitination; when associated with A-57. Ref.15
Mutagenesis571L → A: Increases autoubiquitination; when associated with A-56. Ref.15
Mutagenesis251 – 28434Missing: Abolishes interaction with SMAD2 and SMAD7. Ref.1 Ref.2
Mutagenesis297 – 33034Missing: Abolishes interaction with SMAD7. Ref.1
Mutagenesis5351W → A: Loss of catalytic activity. Ref.13
Mutagenesis5351W → D: Loss of catalytic activity. Ref.13
Mutagenesis5471H → A: Partial loss of catalytic activity. Ref.13
Mutagenesis5471H → F or I: Activates autocatalytic activity. Ref.13
Mutagenesis5811Y → A: Loss of catalytic activity. Ref.13
Mutagenesis7161C → A: Increases Smad7-bound TGF-beta receptors in membrane rafts. Ref.2 Ref.3 Ref.6
Mutagenesis7161C → G: Loss of activity. Loss of ability to ubiquitinate SMAD1 and SMAD2 and no down-regulation of SMAD1 and SMAD2 protein levels. Ref.2 Ref.3 Ref.6
Sequence conflict61G → R in AAG45422. Ref.2

Secondary structure

........................................................................................................... 748
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q9HAU4 [UniParc].

Last modified March 1, 2001. Version 1.
Checksum: 3042B443A3755762

FASTA74886,196
        10         20         30         40         50         60 
MSNPGGRRNG PVKLRLTVLC AKNLVKKDFF RLPDPFAKVV VDGSGQCHST DTVKNTLDPK 

        70         80         90        100        110        120 
WNQHYDLYIG KSDSVTISVW NHKKIHKKQG AGFLGCVRLL SNAINRLKDT GYQRLDLCKL 

       130        140        150        160        170        180 
GPNDNDTVRG QIVVSLQSRD RIGTGGQVVD CSRLFDNDLP DGWEERRTAS GRIQYLNHIT 

       190        200        210        220        230        240 
RTTQWERPTR PASEYSSPGR PLSCFVDENT PISGTNGATC GQSSDPRLAE RRVRSQRHRN 

       250        260        270        280        290        300 
YMSRTHLHTP PDLPEGYEQR TTQQGQVYFL HTQTGVSTWH DPRVPRDLSN INCEELGPLP 

       310        320        330        340        350        360 
PGWEIRNTAT GRVYFVDHNN RTTQFTDPRL SANLHLVLNR QNQLKDQQQQ QVVSLCPDDT 

       370        380        390        400        410        420 
ECLTVPRYKR DLVQKLKILR QELSQQQPQA GHCRIEVSRE EIFEESYRQV MKMRPKDLWK 

       430        440        450        460        470        480 
RLMIKFRGEE GLDYGGVARE WLYLLSHEML NPYYGLFQYS RDDIYTLQIN PDSAVNPEHL 

       490        500        510        520        530        540 
SYFHFVGRIM GMAVFHGHYI DGGFTLPFYK QLLGKSITLD DMELVDPDLH NSLVWILEND 

       550        560        570        580        590        600 
ITGVLDHTFC VEHNAYGEII QHELKPNGKS IPVNEENKKE YVRLYVNWRF LRGIEAQFLA 

       610        620        630        640        650        660 
LQKGFNEVIP QHLLKTFDEK ELELIICGLG KIDVNDWKVN TRLKHCTPDS NIVKWFWKAV 

       670        680        690        700        710        720 
EFFDEERRAR LLQFVTGSSR VPLQGFKALQ GAAGPRLFTI HQIDACTNNL PKAHTCFNRI 

       730        740 
DIPPYESYEK LYEKLLTAIE ETCGFAVE 

« Hide

References

« Hide 'large scale' references
[1]"Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF-beta receptor for degradation."
Kavsak P., Rasmussen R.K., Causing C.G., Bonni S., Zhu H., Thomsen G.H., Wrana J.L.
Mol. Cell 6:1365-1375(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF 251-PRO--VAL-284 AND 297-GLY--LEU-330, INTERACTION WITH SMAD7 AND TGFBR1.
[2]"Smurf2 Is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling."
Lin X., Liang M., Feng X.-H.
J. Biol. Chem. 275:36818-36822(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF 251-PRO--VAL-284 AND CYS-716.
[3]"Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase."
Zhang Y., Chang C., Gehling D.J., Hemmati-Brivanlou A., Derynck R.
Proc. Natl. Acad. Sci. U.S.A. 98:974-979(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF CYS-716.
[4]"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].
Tissue: Brain.
[5]"TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation."
Bonni S., Wang H.R., Causing C.G., Kavsak P., Stroschein S.L., Luo K., Wrana J.L.
Nat. Cell Biol. 3:587-595(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SMAD2; SMAD3 AND SNON.
[6]"Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover."
Di Guglielmo G.M., Le Roy C., Goodfellow A.F., Wrana J.L.
Nat. Cell Biol. 5:410-421(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF CYS-716.
[7]Erratum
Di Guglielmo G.M., Le Roy C., Goodfellow A.F., Wrana J.L.
Nat. Cell Biol. 5:680-680(2003)
[8]"The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase."
Subramaniam V., Li H., Wong M.J., Kitching R., Attisano L., Wrana J., Zubovits J., Burger A.M., Seth A.K.
Br. J. Cancer 89:1538-1544(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RNF11.
[9]"An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein."
Li H., Seth A.K.
Oncogene 23:1801-1808(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH STAMBP AND RNF11.
[10]"AIMP1/p43 downregulates TGF-beta signaling via stabilization of smurf2."
Lee Y.S., Han J.M., Son S.H., Choi J.W., Jeon E.J., Bae S.-C., Park Y.I., Kim S.
Biochem. Biophys. Res. Commun. 371:395-400(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AIMP1.
[11]"Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins."
Mund T., Pelham H.R.
EMBO Rep. 10:501-507(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACTIVATION BY NDFIP1 AND NDFIP2, AUTOUBIQUITINATION.
[12]"SCF(FBXL15) regulates BMP signalling by directing the degradation of HECT-type ubiquitin ligase Smurf1."
Cui Y., He S., Xing C., Lu K., Wang J., Xing G., Meng A., Jia S., He F., Zhang L.
EMBO J. 30:2675-2689(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION.
[13]"Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain."
Ogunjimi A.A., Briant D.J., Pece-Barbara N., Le Roy C., Di Guglielmo G.M., Kavsak P., Rasmussen R.K., Seet B.T., Sicheri F., Wrana J.L.
Mol. Cell 19:297-308(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 369-748, INTERACTION WITH SMAD7, MUTAGENESIS OF TRP-535; HIS-547 AND TYR-581.
[14]"An expanded WW domain recognition motif revealed by the interaction between Smad7 and the E3 ubiquitin ligase Smurf2."
Chong P.A., Lin H., Wrana J.L., Forman-Kay J.D.
J. Biol. Chem. 281:17069-17075(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 297-333 IN COMPLEX WITH SMAD7.
[15]"Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain."
Wiesner S., Ogunjimi A.A., Wang H.R., Rotin D., Sicheri F., Wrana J.L., Forman-Kay J.D.
Cell 130:651-662(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 10-140, AUTOINHIBITION BY C2 DOMAIN, MUTAGENESIS OF PHE-29; PHE-30; THR-56 AND LEU-57.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_073576.1. NM_022739.3.
UniGeneHs.515011.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1ZVDX-ray2.10A369-748[»]
2DJYNMR-A297-333[»]
2JQZNMR-A10-140[»]
2KXQNMR-A250-333[»]
2LTZNMR-A297-333[»]
ProteinModelPortalQ9HAU4.
SMRQ9HAU4. Positions 10-140, 155-745.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid122265. 96 interactions.
DIPDIP-33061N.
IntActQ9HAU4. 65 interactions.
MINTMINT-1180022.
STRING9606.ENSP00000262435.

PTM databases

PhosphoSiteQ9HAU4.

Polymorphism databases

DMDM17865624.

Proteomic databases

PaxDbQ9HAU4.
PRIDEQ9HAU4.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000262435; ENSP00000262435; ENSG00000108854.
ENST00000573633; ENSP00000461327; ENSG00000262909.
GeneID64750.
KEGGhsa:64750.
UCSCuc002jep.1. human.

Organism-specific databases

CTD64750.
GeneCardsGC17M062540.
HGNCHGNC:16809. SMURF2.
MIM605532. gene.
neXtProtNX_Q9HAU4.
PharmGKBPA134985524.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5021.
HOGENOMHOG000208451.
HOVERGENHBG004134.
InParanoidQ9HAU4.
KOK04678.
OMANQAARPF.
PhylomeDBQ9HAU4.
TreeFamTF323658.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.
REACT_71. Gene Expression.
SignaLinkQ9HAU4.
UniPathwayUPA00143.

Gene expression databases

ArrayExpressQ9HAU4.
BgeeQ9HAU4.
CleanExHS_SMURF2.
GenevestigatorQ9HAU4.

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. 3 hits.
[Graphical view]
PIRSFPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
SMARTSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 3 hits.
[Graphical view]
SUPFAMSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 3 hits.
SSF56204. SSF56204. 1 hit.
PROSITEPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 1 hit.
PS50020. WW_DOMAIN_2. 3 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSSMURF2. human.
EvolutionaryTraceQ9HAU4.
GeneWikiSMURF2.
GenomeRNAi64750.
NextBio66708.
PROQ9HAU4.
SOURCESearch...

Entry information

Entry nameSMUF2_HUMAN
AccessionPrimary (citable) accession number: Q9HAU4
Secondary accession number(s): Q52LL1, Q9H260
Entry history
Integrated into UniProtKB/Swiss-Prot: December 13, 2001
Last sequence update: March 1, 2001
Last modified: April 16, 2014
This is version 137 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

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

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM