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A2A5Z6

- SMUF2_MOUSE

UniProt

A2A5Z6 - SMUF2_MOUSE

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Protein

E3 ubiquitin-protein ligase SMURF2

Gene

Smurf2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 4 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. 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 (By similarity).By similarity

Enzyme regulationi

Activated by NDFIP1- and NDFIP2-binding.By similarity

Pathwayi

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei716 – 7161Glycyl thioester intermediatePROSITE-ProRule annotation

GO - Molecular functioni

  1. ligase activity Source: UniProtKB-KW
  2. ubiquitin-protein transferase activity Source: RefGenome

GO - Biological processi

  1. protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: RefGenome
  2. transforming growth factor beta receptor signaling pathway Source: RefGenome
  3. ubiquitin-dependent SMAD protein catabolic process Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiREACT_199115. Antigen processing: Ubiquitination & Proteasome degradation.
REACT_203973. Asymmetric localization of PCP proteins.
REACT_215733. Downregulation of TGF-beta receptor signaling.
REACT_219129. degradation of AXIN.
REACT_220505. Signaling by BMP.
REACT_220566. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase SMURF2 (EC:6.3.2.-)
Alternative name(s):
SMAD ubiquitination regulatory factor 2
SMAD-specific E3 ubiquitin-protein ligase 2
Gene namesi
Name:Smurf2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 11

Organism-specific databases

MGIiMGI:1913563. Smurf2.

Subcellular locationi

Nucleus By similarity. Cytoplasm By similarity. Cell membrane By similarity. Membrane raft By similarity
Note: Cytoplasmic in the presence of SMAD7. Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts. Interacts with STAMBP and RNF11.By similarity

GO - Cellular componenti

  1. cytoplasm Source: RefGenome
  2. nucleus Source: RefGenome
  3. plasma membrane Source: UniProtKB-KW
  4. ubiquitin ligase complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 748748E3 ubiquitin-protein ligase SMURF2PRO_0000358318Add
BLAST

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 (By similarity).By similarity

Keywords - PTMi

Ubl conjugation

Proteomic databases

MaxQBiA2A5Z6.
PaxDbiA2A5Z6.
PRIDEiA2A5Z6.

PTM databases

PhosphoSiteiA2A5Z6.

Expressioni

Inductioni

Up-regulated about ten-fold by activation of the TNF-signaling pathway in vitro.1 Publication

Gene expression databases

BgeeiA2A5Z6.
ExpressionAtlasiA2A5Z6. baseline and differential.
GenevestigatoriA2A5Z6.

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 (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
DVL2O146418EBI-2348309,EBI-740850From a different organism.

Protein-protein interaction databases

BioGridi211376. 19 interactions.
IntActiA2A5Z6. 13 interactions.

Structurei

3D structure databases

ProteinModelPortaliA2A5Z6.
SMRiA2A5Z6. Positions 10-140, 159-192, 249-745.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1 – 9898C2PROSITE-ProRule annotationAdd
BLAST
Domaini157 – 19034WW 1PROSITE-ProRule annotationAdd
BLAST
Domaini251 – 28434WW 2PROSITE-ProRule annotationAdd
BLAST
Domaini297 – 33034WW 3PROSITE-ProRule annotationAdd
BLAST
Domaini414 – 748335HECTPROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi347 – 3515Poly-Gln

Domaini

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

Sequence similaritiesi

Contains 1 C2 domain.PROSITE-ProRule annotation
Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.PROSITE-ProRule annotation
Contains 3 WW domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiCOG5021.
GeneTreeiENSGT00760000118966.
HOGENOMiHOG000208451.
HOVERGENiHBG004134.
InParanoidiA2A5Z6.
KOiK04678.
OMAiNQAARPF.
OrthoDBiEOG77Q4W4.
PhylomeDBiA2A5Z6.
TreeFamiTF323658.

Family and domain databases

Gene3Di2.60.40.150. 1 hit.
InterProiIPR000008. C2_dom.
IPR024928. E3_ub_ligase_SMURF1.
IPR000569. HECT.
IPR001202. WW_dom.
[Graphical view]
PfamiPF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 3 hits.
[Graphical view]
PIRSFiPIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
SMARTiSM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 3 hits.
[Graphical view]
SUPFAMiSSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 3 hits.
SSF56204. SSF56204. 1 hit.
PROSITEiPS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 1 hit.
PS50020. WW_DOMAIN_2. 3 hits.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: A2A5Z6) [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
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 PITGTNGATC GHSSDPRLAE 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
QVVPLCPDDT 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 IPVTEENKKE YVRLYVNWRF LRGIEAQFLA
610 620 630 640 650
LQKGFNEVIP QHLLKTFDEK ELELIICGLG KIDVSDWKVN TRLKHCTPDS
660 670 680 690 700
NVVKWFWKAV EFFDEERRAR LLQFVTGSSR VPLQGFKALQ GAAGPRLFTI
710 720 730 740
HQIDACTNNL PKAHTCFNRI DIPPYESYEK LYEKLLTAIE ETCGFAVE
Length:748
Mass (Da):86,175
Last modified:February 20, 2007 - v1
Checksum:i385AFA32D289D33F
GO
Isoform 2 (identifier: A2A5Z6-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     18-30: Missing.
     31-31: R → G

Show »
Length:735
Mass (Da):84,569
Checksum:iD8C2D02354914238
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti130 – 1301G → V in AAV87906. (PubMed:15820682)Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei18 – 3013Missing in isoform 2. CuratedVSP_036055Add
BLAST
Alternative sequencei31 – 311R → G in isoform 2. CuratedVSP_036056

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AY685230 mRNA. Translation: AAV87906.1.
AL593847 Genomic DNA. Translation: CAM16223.1.
AL593847 Genomic DNA. Translation: CAM16224.1.
CH466558 Genomic DNA. Translation: EDL34316.1.
BC138786 mRNA. Translation: AAI38787.1.
BC138788 mRNA. Translation: AAI38789.1.
CCDSiCCDS25564.1. [A2A5Z6-1]
RefSeqiNP_079757.2. NM_025481.2. [A2A5Z6-1]
XP_006533999.1. XM_006533936.1. [A2A5Z6-2]
UniGeneiMm.340955.

Genome annotation databases

EnsembliENSMUST00000092517; ENSMUSP00000090177; ENSMUSG00000018363. [A2A5Z6-1]
ENSMUST00000103067; ENSMUSP00000099356; ENSMUSG00000018363. [A2A5Z6-2]
ENSMUST00000167787; ENSMUSP00000129269; ENSMUSG00000018363. [A2A5Z6-1]
GeneIDi66313.
KEGGimmu:66313.
UCSCiuc007lzx.2. mouse. [A2A5Z6-1]
uc007lzy.2. mouse. [A2A5Z6-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AY685230 mRNA. Translation: AAV87906.1 .
AL593847 Genomic DNA. Translation: CAM16223.1 .
AL593847 Genomic DNA. Translation: CAM16224.1 .
CH466558 Genomic DNA. Translation: EDL34316.1 .
BC138786 mRNA. Translation: AAI38787.1 .
BC138788 mRNA. Translation: AAI38789.1 .
CCDSi CCDS25564.1. [A2A5Z6-1 ]
RefSeqi NP_079757.2. NM_025481.2. [A2A5Z6-1 ]
XP_006533999.1. XM_006533936.1. [A2A5Z6-2 ]
UniGenei Mm.340955.

3D structure databases

ProteinModelPortali A2A5Z6.
SMRi A2A5Z6. Positions 10-140, 159-192, 249-745.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 211376. 19 interactions.
IntActi A2A5Z6. 13 interactions.

PTM databases

PhosphoSitei A2A5Z6.

Proteomic databases

MaxQBi A2A5Z6.
PaxDbi A2A5Z6.
PRIDEi A2A5Z6.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000092517 ; ENSMUSP00000090177 ; ENSMUSG00000018363 . [A2A5Z6-1 ]
ENSMUST00000103067 ; ENSMUSP00000099356 ; ENSMUSG00000018363 . [A2A5Z6-2 ]
ENSMUST00000167787 ; ENSMUSP00000129269 ; ENSMUSG00000018363 . [A2A5Z6-1 ]
GeneIDi 66313.
KEGGi mmu:66313.
UCSCi uc007lzx.2. mouse. [A2A5Z6-1 ]
uc007lzy.2. mouse. [A2A5Z6-2 ]

Organism-specific databases

CTDi 64750.
MGIi MGI:1913563. Smurf2.

Phylogenomic databases

eggNOGi COG5021.
GeneTreei ENSGT00760000118966.
HOGENOMi HOG000208451.
HOVERGENi HBG004134.
InParanoidi A2A5Z6.
KOi K04678.
OMAi NQAARPF.
OrthoDBi EOG77Q4W4.
PhylomeDBi A2A5Z6.
TreeFami TF323658.

Enzyme and pathway databases

UniPathwayi UPA00143 .
Reactomei REACT_199115. Antigen processing: Ubiquitination & Proteasome degradation.
REACT_203973. Asymmetric localization of PCP proteins.
REACT_215733. Downregulation of TGF-beta receptor signaling.
REACT_219129. degradation of AXIN.
REACT_220505. Signaling by BMP.
REACT_220566. Downregulation of SMAD2/3:SMAD4 transcriptional activity.

Miscellaneous databases

NextBioi 321287.
PROi A2A5Z6.
SOURCEi Search...

Gene expression databases

Bgeei A2A5Z6.
ExpressionAtlasi A2A5Z6. baseline and differential.
Genevestigatori A2A5Z6.

Family and domain databases

Gene3Di 2.60.40.150. 1 hit.
InterProi IPR000008. C2_dom.
IPR024928. E3_ub_ligase_SMURF1.
IPR000569. HECT.
IPR001202. WW_dom.
[Graphical view ]
Pfami PF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 3 hits.
[Graphical view ]
PIRSFi PIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
SMARTi SM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 3 hits.
[Graphical view ]
SUPFAMi SSF49562. SSF49562. 1 hit.
SSF51045. SSF51045. 3 hits.
SSF56204. SSF56204. 1 hit.
PROSITEi PS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 1 hit.
PS50020. WW_DOMAIN_2. 3 hits.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation."
    Yamashita M., Ying S.X., Zhang G.M., Li C., Cheng S.Y., Deng C.X., Zhang Y.E.
    Cell 121:101-113(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    Strain: 129/SvJ.
  2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  3. Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
    Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  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] (ISOFORM 1).
    Tissue: Lung.
  5. "Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts."
    Kaneki H., Guo R., Chen D., Yao Z., Schwarz E.M., Zhang Y.E., Boyce B.F., Xing L.
    J. Biol. Chem. 281:4326-4333(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION BY TNF SIGNALING PATHWAY ACTIVATION.
  6. "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: STABILIZATION BY SCYE1.

Entry informationi

Entry nameiSMUF2_MOUSE
AccessioniPrimary (citable) accession number: A2A5Z6
Secondary accession number(s): A2A5Z7, Q5IRE6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 16, 2008
Last sequence update: February 20, 2007
Last modified: October 29, 2014
This is version 71 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

Level decreases under the suppression of SCYE1, suggesting that SCYE1 stabilizes SMURF2.

Keywords - Technical termi

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. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3