SMUF2_HUMAN
ID SMUF2_HUMAN Reviewed; 748 AA.
AC Q9HAU4; Q52LL1; Q9H260;
DT 13-DEC-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 206.
DE RecName: Full=E3 ubiquitin-protein ligase SMURF2;
DE Short=hSMURF2;
DE EC=2.3.2.26 {ECO:0000269|PubMed:11016919};
DE AltName: Full=HECT-type E3 ubiquitin transferase SMURF2;
DE AltName: Full=SMAD ubiquitination regulatory factor 2;
DE AltName: Full=SMAD-specific E3 ubiquitin-protein ligase 2;
GN Name=SMURF2 {ECO:0000312|HGNC:HGNC:16809};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP FUNCTION, NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF 251-PRO--VAL-284 AND
RP 297-GLY--LEU-330, AND INTERACTION WITH SMAD7 AND TGFBR1.
RX PubMed=11163210; DOI=10.1016/s1097-2765(00)00134-9;
RA Kavsak P., Rasmussen R.K., Causing C.G., Bonni S., Zhu H., Thomsen G.H.,
RA Wrana J.L.;
RT "Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF-
RT beta receptor for degradation.";
RL Mol. Cell 6:1365-1375(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS
RP OF 251-PRO--VAL-284 AND CYS-716.
RX PubMed=11016919; DOI=10.1074/jbc.c000580200;
RA Lin X., Liang M., Feng X.-H.;
RT "Smurf2 Is a ubiquitin E3 ligase mediating proteasome-dependent degradation
RT of Smad2 in transforming growth factor-beta signaling.";
RL J. Biol. Chem. 275:36818-36822(2000).
RN [3]
RP FUNCTION, NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH SMAD1; SMAD2; SMAD3;
RP SMAD6 AND SMAD7, AND MUTAGENESIS OF CYS-716.
RX PubMed=11158580; DOI=10.1073/pnas.98.3.974;
RA Zhang Y., Chang C., Gehling D.J., Hemmati-Brivanlou A., Derynck R.;
RT "Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin
RT ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:974-979(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, AND INTERACTION WITH SMAD2; SMAD3 AND SNON.
RX PubMed=11389444; DOI=10.1038/35078562;
RA Bonni S., Wang H.R., Causing C.G., Kavsak P., Stroschein S.L., Luo K.,
RA Wrana J.L.;
RT "TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that
RT targets SnoN for degradation.";
RL Nat. Cell Biol. 3:587-595(2001).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-716.
RX PubMed=12717440; DOI=10.1038/ncb975;
RA Di Guglielmo G.M., Le Roy C., Goodfellow A.F., Wrana J.L.;
RT "Distinct endocytic pathways regulate TGF-beta receptor signalling and
RT turnover.";
RL Nat. Cell Biol. 5:410-421(2003).
RN [7]
RP ERRATUM OF PUBMED:12717440.
RA Di Guglielmo G.M., Le Roy C., Goodfellow A.F., Wrana J.L.;
RL Nat. Cell Biol. 5:680-680(2003).
RN [8]
RP INTERACTION WITH RNF11.
RX PubMed=14562029; DOI=10.1038/sj.bjc.6601301;
RA Subramaniam V., Li H., Wong M.J., Kitching R., Attisano L., Wrana J.,
RA Zubovits J., Burger A.M., Seth A.K.;
RT "The RING-H2 protein RNF11 is overexpressed in breast cancer and is a
RT target of Smurf2 E3 ligase.";
RL Br. J. Cancer 89:1538-1544(2003).
RN [9]
RP INTERACTION WITH STAMBP AND RNF11.
RX PubMed=14755250; DOI=10.1038/sj.onc.1207319;
RA Li H., Seth A.K.;
RT "An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein.";
RL Oncogene 23:1801-1808(2004).
RN [10]
RP FUNCTION, AND INTERACTION WITH AIMP1.
RX PubMed=18448069; DOI=10.1016/j.bbrc.2008.04.099;
RA Lee Y.S., Han J.M., Son S.H., Choi J.W., Jeon E.J., Bae S.-C., Park Y.I.,
RA Kim S.;
RT "AIMP1/p43 downregulates TGF-beta signaling via stabilization of smurf2.";
RL Biochem. Biophys. Res. Commun. 371:395-400(2008).
RN [11]
RP ACTIVATION BY NDFIP1 AND NDFIP2, AND AUTO-UBIQUITINATION.
RX PubMed=19343052; DOI=10.1038/embor.2009.30;
RA Mund T., Pelham H.R.;
RT "Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP
RT proteins.";
RL EMBO Rep. 10:501-507(2009).
RN [12]
RP UBIQUITINATION.
RX PubMed=21572392; DOI=10.1038/emboj.2011.155;
RA Cui Y., He S., Xing C., Lu K., Wang J., Xing G., Meng A., Jia S., He F.,
RA Zhang L.;
RT "SCF(FBXL15) regulates BMP signalling by directing the degradation of HECT-
RT type ubiquitin ligase Smurf1.";
RL EMBO J. 30:2675-2689(2011).
RN [13]
RP FUNCTION, INTERACTION WITH TTC3, UBIQUITINATION, AND MUTAGENESIS OF
RP 29-PHE-PHE-30 AND CYS-716.
RX PubMed=30696809; DOI=10.1038/s41419-019-1308-8;
RA Kim J.H., Ham S., Lee Y., Suh G.Y., Lee Y.S.;
RT "TTC3 contributes to TGF-beta1-induced epithelial-mesenchymal transition
RT and myofibroblast differentiation, potentially through SMURF2
RT ubiquitylation and degradation.";
RL Cell Death Dis. 10:92-92(2019).
RN [14]
RP FUNCTION (MICROBIAL INFECTION), INTERACTION WITH EBOV AND MARV PROTEIN VP40
RP (MICROBIAL INFECTION), DOMAIN (MICROBIAL INFECTION), AND MUTAGENESIS OF
RP CYS-716.
RX PubMed=33673144; DOI=10.3390/v13020288;
RA Shepley-McTaggart A., Schwoerer M.P., Sagum C.A., Bedford M.T.,
RA Jaladanki C.K., Fan H., Cassel J., Harty R.N.;
RT "Ubiquitin Ligase SMURF2 Interacts with Filovirus VP40 and Promotes Egress
RT of VP40 VLPs.";
RL Viruses 13:0-0(2021).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 369-748, INTERACTION WITH SMAD7,
RP AND MUTAGENESIS OF TRP-535; HIS-547 AND TYR-581.
RX PubMed=16061177; DOI=10.1016/j.molcel.2005.06.028;
RA Ogunjimi A.A., Briant D.J., Pece-Barbara N., Le Roy C., Di Guglielmo G.M.,
RA Kavsak P., Rasmussen R.K., Seet B.T., Sicheri F., Wrana J.L.;
RT "Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the
RT HECT domain.";
RL Mol. Cell 19:297-308(2005).
RN [16]
RP STRUCTURE BY NMR OF 297-333 IN COMPLEX WITH SMAD7.
RX PubMed=16641086; DOI=10.1074/jbc.m601493200;
RA Chong P.A., Lin H., Wrana J.L., Forman-Kay J.D.;
RT "An expanded WW domain recognition motif revealed by the interaction
RT between Smad7 and the E3 ubiquitin ligase Smurf2.";
RL J. Biol. Chem. 281:17069-17075(2006).
RN [17]
RP UBIQUITINATION BY TRAF4.
RX PubMed=31076633; DOI=10.1038/s41418-019-0328-3;
RA Li J., Wang P., Xie Z., Wang S., Cen S., Li M., Liu W., Tang S., Ye G.,
RA Zheng G., Su H., Ma M., Wu X., Wu Y., Shen H.;
RT "TRAF4 positively regulates the osteogenic differentiation of mesenchymal
RT stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2.";
RL Cell Death Differ. 26:2652-2666(2019).
RN [18]
RP STRUCTURE BY NMR OF 10-140, AUTOINHIBITION BY C2 DOMAIN, AND MUTAGENESIS OF
RP 29-PHE-PHE-30; THR-56 AND LEU-57.
RX PubMed=17719543; DOI=10.1016/j.cell.2007.06.050;
RA Wiesner S., Ogunjimi A.A., Wang H.R., Rotin D., Sicheri F., Wrana J.L.,
RA Forman-Kay J.D.;
RT "Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2
RT domain.";
RL Cell 130:651-662(2007).
CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an
CC E2 ubiquitin-conjugating enzyme in the form of a thioester and then
CC directly transfers the ubiquitin to targeted substrates
CC (PubMed:11016919). Interacts with SMAD7 to trigger SMAD7-mediated
CC transforming growth factor beta/TGF-beta receptor ubiquitin-dependent
CC degradation, thereby down-regulating TGF-beta signaling
CC (PubMed:11163210, PubMed:12717440). In addition, interaction with SMAD7
CC activates autocatalytic degradation, which is prevented by interaction
CC with AIMP1 (PubMed:18448069). Also forms a stable complex with TGF-beta
CC receptor-mediated phosphorylated SMAD1, SMAD2 and SMAD3, and targets
CC SMAD1 and SMAD2 for ubiquitination and proteasome-mediated degradation
CC (PubMed:11016919, PubMed:11158580, PubMed:11389444). SMAD2 may recruit
CC substrates, such as SNON, for ubiquitin-dependent degradation
CC (PubMed:11389444). Negatively regulates TGFB1-induced epithelial-
CC mesenchymal transition and myofibroblast differentiation
CC (PubMed:30696809). {ECO:0000269|PubMed:11016919,
CC ECO:0000269|PubMed:11158580, ECO:0000269|PubMed:11163210,
CC ECO:0000269|PubMed:11389444, ECO:0000269|PubMed:12717440,
CC ECO:0000269|PubMed:18448069, ECO:0000269|PubMed:30696809}.
CC -!- FUNCTION: (Microbial infection) In case of filoviruses Ebola/EBOV and
CC Marburg/MARV infection, the complex formed by viral matrix protein VP40
CC and SMURF2 facilitates virus budding. {ECO:0000269|PubMed:33673144}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.26; Evidence={ECO:0000269|PubMed:11016919};
CC -!- ACTIVITY REGULATION: Activated by NDFIP1- and NDFIP2-binding.
CC {ECO:0000269|PubMed:19343052}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts (via WW domains) with SMAD1 (PubMed:11158580).
CC Interacts (via WW domains) with SMAD2 (via PY-motif) (PubMed:11158580,
CC PubMed:11389444). Interacts (via WW domains) with SMAD3 (via PY-motif)
CC (PubMed:11158580, PubMed:11389444). Interacts with SMAD6
CC (PubMed:11158580). Interacts with SMAD7 (via PY-motif) and TGFBR1;
CC SMAD7 recruits SMURF2 to the TGF-beta receptor and regulates its
CC degradation (PubMed:11163210, PubMed:11158580, PubMed:33673144,
CC PubMed:16061177, PubMed:16641086). Does not interact with SMAD4; SMAD4
CC lacks a PY-motif (PubMed:11158580). Interacts with AIMP1
CC (PubMed:18448069). Interacts with SNON (PubMed:11389444). Interacts
CC with STAMBP and RNF11 (PubMed:14562029, PubMed:14755250). May interact
CC with NDFIP1 and NDFIP2; this interaction induces the E3 ubiquitin-
CC protein ligase activity. Interacts with TTC3 (Probable).
CC {ECO:0000269|PubMed:11158580, ECO:0000269|PubMed:11163210,
CC ECO:0000269|PubMed:11389444, ECO:0000269|PubMed:14562029,
CC ECO:0000269|PubMed:14755250, ECO:0000269|PubMed:16061177,
CC ECO:0000269|PubMed:16641086, ECO:0000269|PubMed:18448069,
CC ECO:0000269|PubMed:33673144, ECO:0000305|PubMed:30696809}.
CC -!- SUBUNIT: (Microbial infection) Interacts (via WW domains) with EBOV and
CC MARV VP40 (via PPXY motif); the interaction facilitates VP40 virus-like
CC particle budding. {ECO:0000269|PubMed:33673144}.
CC -!- INTERACTION:
CC Q9HAU4; Q9H469: FBXL15; NbExp=3; IntAct=EBI-396727, EBI-6144096;
CC Q9HAU4; P46934-4: NEDD4; NbExp=2; IntAct=EBI-396727, EBI-16129814;
CC Q9HAU4; Q9Y3C5: RNF11; NbExp=5; IntAct=EBI-396727, EBI-396669;
CC Q9HAU4; Q8WWV3: RTN4IP1; NbExp=3; IntAct=EBI-396727, EBI-743502;
CC Q9HAU4; Q15797: SMAD1; NbExp=6; IntAct=EBI-396727, EBI-1567153;
CC Q9HAU4; Q15796: SMAD2; NbExp=6; IntAct=EBI-396727, EBI-1040141;
CC Q9HAU4; P84022: SMAD3; NbExp=8; IntAct=EBI-396727, EBI-347161;
CC Q9HAU4; O15105: SMAD7; NbExp=7; IntAct=EBI-396727, EBI-3861591;
CC Q9HAU4; Q9HAU4: SMURF2; NbExp=6; IntAct=EBI-396727, EBI-396727;
CC Q9HAU4; P53804: TTC3; NbExp=2; IntAct=EBI-396727, EBI-2681313;
CC Q9HAU4; P0CG47: UBB; NbExp=4; IntAct=EBI-396727, EBI-413034;
CC Q9HAU4; PRO_0000037548 [Q9WMX2]; Xeno; NbExp=2; IntAct=EBI-396727, EBI-6863741;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12717440}. Cytoplasm
CC {ECO:0000269|PubMed:12717440}. Cell membrane
CC {ECO:0000269|PubMed:12717440}. Membrane raft
CC {ECO:0000269|PubMed:12717440}. Note=Cytoplasmic in the presence of
CC SMAD7. Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane
CC rafts.
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DOMAIN: The second and third WW domains are responsible for interaction
CC with the PY-motif of R-SMAD (SMAD1, SMAD2 and SMAD3).
CC -!- DOMAIN: The C2 domain is involved in autoinhibition of the catalytic
CC activity by interacting with the HECT domain.
CC -!- DOMAIN: (Microbial infection) The WW domains mediate binding with
CC matrix protein VP40. {ECO:0000269|PubMed:33673144}.
CC -!- PTM: Auto-ubiquitinated and ubiquitinated in the presence of RNF11 and
CC UBE2D1 (PubMed:19343052, PubMed:30696809). Ubiquitinated by the
CC SCF(FBXL15) complex and TTC3, leading to its degradation by the
CC proteasome (PubMed:21572392, PubMed:30696809). 'Lys-48'-linked
CC polyubiquitination mediated by TRAF4 at Lys-119 leads to SMURF2
CC proteasomal degradation (PubMed:31076633).
CC {ECO:0000269|PubMed:19343052, ECO:0000269|PubMed:21572392,
CC ECO:0000269|PubMed:30696809, ECO:0000269|PubMed:31076633}.
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DR EMBL; AF310676; AAG45422.1; -; mRNA.
DR EMBL; AF301463; AAG25641.1; -; mRNA.
DR EMBL; AY014180; AAG50421.1; -; mRNA.
DR EMBL; BC093876; AAH93876.1; -; mRNA.
DR EMBL; BC111945; AAI11946.1; -; mRNA.
DR CCDS; CCDS32707.1; -.
DR RefSeq; NP_073576.1; NM_022739.3.
DR PDB; 1ZVD; X-ray; 2.10 A; A=369-748.
DR PDB; 2DJY; NMR; -; A=297-333.
DR PDB; 2JQZ; NMR; -; A=10-140.
DR PDB; 2KXQ; NMR; -; A=250-333.
DR PDB; 2LTZ; NMR; -; A=297-333.
DR PDB; 6FX4; X-ray; 2.50 A; A/C=631-745.
DR PDB; 7M3Q; X-ray; 2.50 A; A=366-748.
DR PDBsum; 1ZVD; -.
DR PDBsum; 2DJY; -.
DR PDBsum; 2JQZ; -.
DR PDBsum; 2KXQ; -.
DR PDBsum; 2LTZ; -.
DR PDBsum; 6FX4; -.
DR PDBsum; 7M3Q; -.
DR AlphaFoldDB; Q9HAU4; -.
DR BMRB; Q9HAU4; -.
DR SMR; Q9HAU4; -.
DR BioGRID; 122265; 175.
DR CORUM; Q9HAU4; -.
DR DIP; DIP-33061N; -.
DR IntAct; Q9HAU4; 75.
DR MINT; Q9HAU4; -.
DR STRING; 9606.ENSP00000262435; -.
DR ChEMBL; CHEMBL4523460; -.
DR iPTMnet; Q9HAU4; -.
DR PhosphoSitePlus; Q9HAU4; -.
DR BioMuta; SMURF2; -.
DR DMDM; 17865624; -.
DR EPD; Q9HAU4; -.
DR jPOST; Q9HAU4; -.
DR MassIVE; Q9HAU4; -.
DR MaxQB; Q9HAU4; -.
DR PaxDb; Q9HAU4; -.
DR PeptideAtlas; Q9HAU4; -.
DR PRIDE; Q9HAU4; -.
DR ProteomicsDB; 81439; -.
DR Antibodypedia; 31598; 346 antibodies from 34 providers.
DR DNASU; 64750; -.
DR Ensembl; ENST00000262435.14; ENSP00000262435.9; ENSG00000108854.16.
DR GeneID; 64750; -.
DR KEGG; hsa:64750; -.
DR MANE-Select; ENST00000262435.14; ENSP00000262435.9; NM_022739.4; NP_073576.1.
DR UCSC; uc002jep.2; human.
DR CTD; 64750; -.
DR DisGeNET; 64750; -.
DR GeneCards; SMURF2; -.
DR HGNC; HGNC:16809; SMURF2.
DR HPA; ENSG00000108854; Low tissue specificity.
DR MIM; 605532; gene.
DR neXtProt; NX_Q9HAU4; -.
DR OpenTargets; ENSG00000108854; -.
DR PharmGKB; PA134985524; -.
DR VEuPathDB; HostDB:ENSG00000108854; -.
DR eggNOG; KOG0940; Eukaryota.
DR GeneTree; ENSGT00940000155563; -.
DR HOGENOM; CLU_002173_1_1_1; -.
DR InParanoid; Q9HAU4; -.
DR OMA; TRPACEY; -.
DR OrthoDB; 167687at2759; -.
DR PhylomeDB; Q9HAU4; -.
DR TreeFam; TF323658; -.
DR BRENDA; 2.3.2.26; 2681.
DR PathwayCommons; Q9HAU4; -.
DR Reactome; R-HSA-201451; Signaling by BMP.
DR Reactome; R-HSA-2173788; Downregulation of TGF-beta receptor signaling.
DR Reactome; R-HSA-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
DR Reactome; R-HSA-4608870; Asymmetric localization of PCP proteins.
DR Reactome; R-HSA-4641257; Degradation of AXIN.
DR Reactome; R-HSA-5632684; Hedgehog 'on' state.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-8941858; Regulation of RUNX3 expression and activity.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; Q9HAU4; -.
DR SIGNOR; Q9HAU4; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 64750; 41 hits in 1118 CRISPR screens.
DR ChiTaRS; SMURF2; human.
DR EvolutionaryTrace; Q9HAU4; -.
DR GeneWiki; SMURF2; -.
DR GenomeRNAi; 64750; -.
DR Pharos; Q9HAU4; Tchem.
DR PRO; PR:Q9HAU4; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q9HAU4; protein.
DR Bgee; ENSG00000108854; Expressed in buccal mucosa cell and 205 other tissues.
DR ExpressionAtlas; Q9HAU4; baseline and differential.
DR Genevisible; Q9HAU4; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045121; C:membrane raft; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046332; F:SMAD binding; IPI:BHF-UCL.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:Reactome.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; NAS:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:CACAO.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; TAS:Reactome.
DR GO; GO:1901165; P:positive regulation of trophoblast cell migration; IDA:CACAO.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0000209; P:protein polyubiquitination; IBA:GO_Central.
DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR GO; GO:0017015; P:regulation of transforming growth factor beta receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR GO; GO:0030579; P:ubiquitin-dependent SMAD protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0060071; P:Wnt signaling pathway, planar cell polarity pathway; TAS:Reactome.
DR CDD; cd00078; HECTc; 1.
DR CDD; cd00201; WW; 3.
DR Gene3D; 2.60.40.150; -; 1.
DR IDEAL; IID00223; -.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR024928; E3_ub_ligase_SMURF1.
DR InterPro; IPR000569; HECT_dom.
DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR InterPro; IPR001202; WW_dom.
DR InterPro; IPR036020; WW_dom_sf.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF00397; WW; 3.
DR PIRSF; PIRSF001569; E3_ub_ligase_SMURF1; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00456; WW; 3.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF51045; SSF51045; 3.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS01159; WW_DOMAIN_1; 1.
DR PROSITE; PS50020; WW_DOMAIN_2; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Cytoplasm; Host-virus interaction;
KW Isopeptide bond; Membrane; Nucleus; Reference proteome; Repeat;
KW Transferase; Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..748
FT /note="E3 ubiquitin-protein ligase SMURF2"
FT /id="PRO_0000120329"
FT DOMAIN 1..119
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 157..190
FT /note="WW 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 251..284
FT /note="WW 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 297..330
FT /note="WW 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224"
FT DOMAIN 414..748
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT ACT_SITE 716
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT CROSSLNK 119
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:31076633"
FT MUTAGEN 29..30
FT /note="FF->AA: Increases auto-ubiquitination."
FT /evidence="ECO:0000269|PubMed:17719543,
FT ECO:0000269|PubMed:30696809"
FT MUTAGEN 56
FT /note="T->A: Increases auto-ubiquitination; when associated
FT with A-57."
FT /evidence="ECO:0000269|PubMed:17719543"
FT MUTAGEN 57
FT /note="L->A: Increases auto-ubiquitination; when associated
FT with A-56."
FT /evidence="ECO:0000269|PubMed:17719543"
FT MUTAGEN 251..284
FT /note="Missing: Abolishes interaction with SMAD2 and
FT SMAD7."
FT /evidence="ECO:0000269|PubMed:11016919,
FT ECO:0000269|PubMed:11163210"
FT MUTAGEN 297..330
FT /note="Missing: Abolishes interaction with SMAD7."
FT /evidence="ECO:0000269|PubMed:11163210"
FT MUTAGEN 535
FT /note="W->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:16061177"
FT MUTAGEN 535
FT /note="W->D: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:16061177"
FT MUTAGEN 547
FT /note="H->A: Partial loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:16061177"
FT MUTAGEN 547
FT /note="H->F,I: Activates autocatalytic activity."
FT /evidence="ECO:0000269|PubMed:16061177"
FT MUTAGEN 581
FT /note="Y->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:16061177"
FT MUTAGEN 716
FT /note="C->A: Loss of catalytic activity. Increases SMAD7-
FT bound TGF-beta receptors in membrane rafts. Decreases
FT interaction with TTC3. Decreased VP40 virus-like particle
FT budding."
FT /evidence="ECO:0000269|PubMed:11016919,
FT ECO:0000269|PubMed:11158580, ECO:0000269|PubMed:12717440,
FT ECO:0000269|PubMed:30696809, ECO:0000269|PubMed:33673144"
FT MUTAGEN 716
FT /note="C->G: Loss of activity. Loss of ability to
FT ubiquitinate SMAD1 and SMAD2 and no down-regulation of
FT SMAD1 and SMAD2 protein levels."
FT /evidence="ECO:0000269|PubMed:11016919,
FT ECO:0000269|PubMed:11158580, ECO:0000269|PubMed:12717440"
FT CONFLICT 6
FT /note="G -> R (in Ref. 2; AAG45422)"
FT /evidence="ECO:0000305"
FT STRAND 12..23
FT /evidence="ECO:0007829|PDB:2JQZ"
FT STRAND 35..41
FT /evidence="ECO:0007829|PDB:2JQZ"
FT TURN 42..44
FT /evidence="ECO:0007829|PDB:2JQZ"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:2JQZ"
FT STRAND 60..69
FT /evidence="ECO:0007829|PDB:2JQZ"
FT STRAND 75..81
FT /evidence="ECO:0007829|PDB:2JQZ"
FT HELIX 82..87
FT /evidence="ECO:0007829|PDB:2JQZ"
FT STRAND 93..99
FT /evidence="ECO:0007829|PDB:2JQZ"
FT HELIX 101..110
FT /evidence="ECO:0007829|PDB:2JQZ"
FT STRAND 113..115
FT /evidence="ECO:0007829|PDB:2JQZ"
FT STRAND 131..138
FT /evidence="ECO:0007829|PDB:2JQZ"
FT STRAND 258..262
FT /evidence="ECO:0007829|PDB:2KXQ"
FT TURN 263..265
FT /evidence="ECO:0007829|PDB:2KXQ"
FT STRAND 266..271
FT /evidence="ECO:0007829|PDB:2KXQ"
FT TURN 272..275
FT /evidence="ECO:0007829|PDB:2KXQ"
FT STRAND 276..280
FT /evidence="ECO:0007829|PDB:2KXQ"
FT STRAND 282..284
FT /evidence="ECO:0007829|PDB:2KXQ"
FT STRAND 286..288
FT /evidence="ECO:0007829|PDB:2KXQ"
FT HELIX 293..295
FT /evidence="ECO:0007829|PDB:2KXQ"
FT STRAND 301..307
FT /evidence="ECO:0007829|PDB:2DJY"
FT STRAND 309..311
FT /evidence="ECO:0007829|PDB:2DJY"
FT STRAND 313..317
FT /evidence="ECO:0007829|PDB:2DJY"
FT TURN 318..321
FT /evidence="ECO:0007829|PDB:2DJY"
FT STRAND 322..326
FT /evidence="ECO:0007829|PDB:2DJY"
FT TURN 328..330
FT /evidence="ECO:0007829|PDB:2DJY"
FT HELIX 372..386
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 392..397
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 402..411
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 415..419
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 420..426
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 434..449
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 452..454
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 455..460
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 463..469
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 473..475
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 479..495
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 506..512
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 522..525
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 527..538
FT /evidence="ECO:0007829|PDB:1ZVD"
FT TURN 542..544
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 549..555
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 558..565
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 568..570
FT /evidence="ECO:0007829|PDB:7M3Q"
FT TURN 574..577
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 578..590
FT /evidence="ECO:0007829|PDB:1ZVD"
FT TURN 591..594
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 595..608
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 611..614
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 619..627
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 629..631
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 634..639
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 641..646
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 651..662
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 665..676
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 679..681
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 686..688
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 692..695
FT /evidence="ECO:0007829|PDB:7M3Q"
FT STRAND 698..702
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 712..714
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 715..717
FT /evidence="ECO:0007829|PDB:1ZVD"
FT STRAND 719..722
FT /evidence="ECO:0007829|PDB:1ZVD"
FT HELIX 728..739
FT /evidence="ECO:0007829|PDB:1ZVD"
SQ SEQUENCE 748 AA; 86196 MW; 3042B443A3755762 CRC64;
MSNPGGRRNG PVKLRLTVLC AKNLVKKDFF RLPDPFAKVV VDGSGQCHST DTVKNTLDPK
WNQHYDLYIG KSDSVTISVW NHKKIHKKQG AGFLGCVRLL SNAINRLKDT GYQRLDLCKL
GPNDNDTVRG QIVVSLQSRD RIGTGGQVVD CSRLFDNDLP DGWEERRTAS GRIQYLNHIT
RTTQWERPTR PASEYSSPGR PLSCFVDENT PISGTNGATC GQSSDPRLAE RRVRSQRHRN
YMSRTHLHTP PDLPEGYEQR TTQQGQVYFL HTQTGVSTWH DPRVPRDLSN INCEELGPLP
PGWEIRNTAT GRVYFVDHNN RTTQFTDPRL SANLHLVLNR QNQLKDQQQQ QVVSLCPDDT
ECLTVPRYKR DLVQKLKILR QELSQQQPQA GHCRIEVSRE EIFEESYRQV MKMRPKDLWK
RLMIKFRGEE GLDYGGVARE WLYLLSHEML NPYYGLFQYS RDDIYTLQIN PDSAVNPEHL
SYFHFVGRIM GMAVFHGHYI DGGFTLPFYK QLLGKSITLD DMELVDPDLH NSLVWILEND
ITGVLDHTFC VEHNAYGEII QHELKPNGKS IPVNEENKKE YVRLYVNWRF LRGIEAQFLA
LQKGFNEVIP QHLLKTFDEK ELELIICGLG KIDVNDWKVN TRLKHCTPDS NIVKWFWKAV
EFFDEERRAR LLQFVTGSSR VPLQGFKALQ GAAGPRLFTI HQIDACTNNL PKAHTCFNRI
DIPPYESYEK LYEKLLTAIE ETCGFAVE
