A2A5Z6 (SMUF2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:

Smurf2

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	748 AA.
Sequence status	Complete.
Protein existence	Evidence 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 By similarity.
Enzyme regulation	Activated by NDFIP1- and NDFIP2-binding By similarity.
Pathway	Protein modification; protein ubiquitination. Ref.5
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 By similarity. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase By similarity.
Subcellular location	Nucleus By similarity. Cytoplasm By similarity. Cell membrane By similarity. Membrane raft By similarity. Note: Cytoplasmic in the presence of SMAD7 By similarity. Co-localizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts By similarity. Interacts with STAMBP and RNF11 By similarity.
Induction	Up-regulated about ten-fold by activation of the TNF-signaling pathway in vitro. Ref.5
Domain	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.
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 By similarity.
Miscellaneous	Level decreases under the suppression of SCYE1, suggesting that SCYE1 stabilizes SMURF2.
Sequence similarities	Contains 1 C2 domain. Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. Contains 3 WW domains.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
Molecular function	Ligase
PTM	Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	protein ubiquitination involved in ubiquitin-dependent protein catabolic process Inferred from Biological aspect of Ancestor. Source: RefGenome transforming growth factor beta receptor signaling pathway Inferred from Biological aspect of Ancestor. Source: RefGenome ubiquitin-dependent SMAD protein catabolic process Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from Biological aspect of Ancestor. Source: RefGenome membrane raft Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from Biological aspect of Ancestor. Source: RefGenome plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell ubiquitin ligase complex Inferred from electronic annotation. Source: Compara
Molecular_function	ubiquitin-protein ligase activity Inferred from Biological aspect of Ancestor. Source: RefGenome
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DVL2	O14641	8	EBI-2348309,EBI-740850	From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: A2A5Z6-1)

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.

Isoform 2 (identifier: A2A5Z6-2)

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 748	748	E3 ubiquitin-protein ligase SMURF2		PRO_0000358318
Regions
	Domain	1 – 98	98	C2
	Domain	157 – 190	34	WW 1
	Domain	251 – 284	34	WW 2
	Domain	297 – 330	34	WW 3
	Domain	414 – 748	335	HECT
	Compositional bias	347 – 351	5	Poly-Gln
Sites
	Active site	716	1	Glycyl thioester intermediate By similarity
Natural variations
	Alternative sequence	18 – 30	13	Missing in isoform 2.		VSP_036055
	Alternative sequence	31	1	R → G in isoform 2.		VSP_036056
Experimental info
	Sequence conflict	130	1	G → V in AAV87906. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 20, 2007. Version 1. Checksum: 385AFA32D289D33F	FASTA	748	86,175
	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 PITGTNGATC GHSSDPRLAE RRVRSQRHRN 250 260 270 280 290 300 YMSRTHLHTP PDLPEGYEQR TTQQGQVYFL HTQTGVSTWH DPRVPRDLSN INCEELGPLP 310 320 330 340 350 360 PGWEIRNTAT GRVYFVDHNN RTTQFTDPRL SANLHLVLNR QNQLKDQQQQ QVVPLCPDDT 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 IPVTEENKKE YVRLYVNWRF LRGIEAQFLA 610 620 630 640 650 660 LQKGFNEVIP QHLLKTFDEK ELELIICGLG KIDVSDWKVN TRLKHCTPDS NVVKWFWKAV 670 680 690 700 710 720 EFFDEERRAR LLQFVTGSSR VPLQGFKALQ GAAGPRLFTI HQIDACTNNL PKAHTCFNRI 730 740 DIPPYESYEK LYEKLLTAIE ETCGFAVE
	Isoform 2 [UniParc]. Checksum: D8C2D02354914238	FASTA	735	84,569
	10 20 30 40 50 60 MSNPGGRRNG PVKLRLTGLP DPFAKVVVDG SGQCHSTDTV KNTLDPKWNQ HYDLYIGKSD 70 80 90 100 110 120 SVTISVWNHK KIHKKQGAGF LGCVRLLSNA INRLKDTGYQ RLDLCKLGPN DNDTVRGQIV 130 140 150 160 170 180 VSLQSRDRIG TGGQVVDCSR LFDNDLPDGW EERRTASGRI QYLNHITRTT QWERPTRPAS 190 200 210 220 230 240 EYSSPGRPLS CFVDENTPIT GTNGATCGHS SDPRLAERRV RSQRHRNYMS RTHLHTPPDL 250 260 270 280 290 300 PEGYEQRTTQ QGQVYFLHTQ TGVSTWHDPR VPRDLSNINC EELGPLPPGW EIRNTATGRV 310 320 330 340 350 360 YFVDHNNRTT QFTDPRLSAN LHLVLNRQNQ LKDQQQQQVV PLCPDDTECL TVPRYKRDLV 370 380 390 400 410 420 QKLKILRQEL SQQQPQAGHC RIEVSREEIF EESYRQVMKM RPKDLWKRLM IKFRGEEGLD 430 440 450 460 470 480 YGGVAREWLY LLSHEMLNPY YGLFQYSRDD IYTLQINPDS AVNPEHLSYF HFVGRIMGMA 490 500 510 520 530 540 VFHGHYIDGG FTLPFYKQLL GKSITLDDME LVDPDLHNSL VWILENDITG VLDHTFCVEH 550 560 570 580 590 600 NAYGEIIQHE LKPNGKSIPV TEENKKEYVR LYVNWRFLRG IEAQFLALQK GFNEVIPQHL 610 620 630 640 650 660 LKTFDEKELE LIICGLGKID VSDWKVNTRL KHCTPDSNVV KWFWKAVEFF DEERRARLLQ 670 680 690 700 710 720 FVTGSSRVPL QGFKALQGAA GPRLFTIHQI DACTNNLPKA HTCFNRIDIP PYESYEKLYE 730 KLLTAIEETC GFAVE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] 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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00346033. IPI00626426.
RefSeq	NP_079757.2. NM_025481.2.
UniGene	Mm.340955.
3D structure databases
ProteinModelPortal	A2A5Z6.
SMR	A2A5Z6. Positions 10-140, 159-192, 249-742.
ModBase	Search...
Protein-protein interaction databases
IntAct	A2A5Z6. 13 interactions.
PTM databases
PhosphoSite	A2A5Z6.
Proteomic databases
PaxDb	A2A5Z6.
PRIDE	A2A5Z6.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000092517; ENSMUSP00000090177; ENSMUSG00000018363. ENSMUST00000103067; ENSMUSP00000099356; ENSMUSG00000018363. ENSMUST00000167787; ENSMUSP00000129269; ENSMUSG00000018363.
GeneID	66313.
KEGG	mmu:66313.
UCSC	uc007lzx.2. mouse. uc007lzy.2. mouse.
Organism-specific databases
CTD	64750.
MGI	MGI:1913563. Smurf2.
Phylogenomic databases
eggNOG	COG5021.
GeneTree	ENSGT00670000098006.
HOGENOM	HOG000208451.
HOVERGEN	HBG004134.
InParanoid	Q5IRE6.
KO	K04678.
OMA	ANQAARP.
Enzyme and pathway databases
UniPathway	UPA00143.
Gene expression databases
ArrayExpress	A2A5Z6.
Bgee	A2A5Z6.
Genevestigator	A2A5Z6.
Family and domain databases
InterPro	IPR000008. C2_Ca-dep. IPR008973. C2_Ca/lipid-bd_dom_CaLB. IPR018029. C2_membr_targeting. IPR024928. E3_ub_ligase_SMURF1. IPR000569. HECT. IPR001202. WW_dom. [Graphical view]
Pfam	PF00168. C2. 1 hit. PF00632. HECT. 1 hit. PF00397. WW. 3 hits. [Graphical view]
PIRSF	PIRSF001569. E3_ub_ligase_SMURF1. 1 hit.
SMART	SM00239. C2. 1 hit. SM00119. HECTc. 1 hit. SM00456. WW. 3 hits. [Graphical view]
SUPFAM	SSF49562. C2_CaLB. 1 hit. SSF56204. HECT. 1 hit. SSF51045. WW_Rsp5_WWP. 3 hits.
PROSITE	PS50004. C2. 1 hit. PS50237. HECT. 1 hit. PS01159. WW_DOMAIN_1. 1 hit. PS50020. WW_DOMAIN_2. 3 hits. [Graphical view]
ProtoNet	Search...
Other
NextBio	321287.
SOURCE	Search...

Entry information

Entry name

SMUF2_MOUSE

Accession

Primary (citable) accession number: A2A5Z6
Secondary accession number(s): A2A5Z7, Q5IRE6

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 16, 2008
Last sequence update:	February 20, 2007
Last modified:	May 1, 2013
This is version 57 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program