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| | ==Smurf1 WW2 domain in complex with a Smad7 derived peptide== | | ==Smurf1 WW2 domain in complex with a Smad7 derived peptide== |
| - | <StructureSection load='2ltx' size='340' side='right'caption='[[2ltx]], [[NMR_Ensembles_of_Models | 25 NMR models]]' scene=''> | + | <StructureSection load='2ltx' size='340' side='right'caption='[[2ltx]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2ltx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LTX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LTX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2ltx]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LTX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LTX FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2ltv|2ltv]], [[2ltw|2ltw]], [[2lty|2lty]], [[2ltz|2ltz]]</div></td></tr> | + | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ltx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ltx OCA], [https://pdbe.org/2ltx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ltx RCSB], [https://www.ebi.ac.uk/pdbsum/2ltx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ltx ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMURF1, KIAA1625 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ltx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ltx OCA], [https://pdbe.org/2ltx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ltx RCSB], [https://www.ebi.ac.uk/pdbsum/2ltx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ltx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[https://www.uniprot.org/uniprot/SMAD7_HUMAN SMAD7_HUMAN]] Genetic variations in SMAD7 influence susceptibility to colorectal cancer type 3 (CRCS3) [MIM:[https://omim.org/entry/612229 612229]]. Colorectal cancer consists of tumors or cancer of either the colon or rectum or both. Cancers of the large intestine are the second most common form of cancer found in males and females. Symptoms include rectal bleeding, occult blood in stools, bowel obstruction and weight loss. Treatment is based largely on the extent of cancer penetration into the intestinal wall. Surgical cures are possible if the malignancy is confined to the intestine. Risk can be reduced when following a diet which is low in fat and high in fiber.<ref>PMID:17934461</ref> | |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/SMUF1_HUMAN SMUF1_HUMAN]] E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA.<ref>PMID:10458166</ref> <ref>PMID:19937093</ref> <ref>PMID:21402695</ref> [[https://www.uniprot.org/uniprot/SMAD7_HUMAN SMAD7_HUMAN]] Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator (By similarity).<ref>PMID:9892009</ref> <ref>PMID:11163210</ref> <ref>PMID:12023024</ref> <ref>PMID:14718519</ref> <ref>PMID:17327236</ref>
| + | [https://www.uniprot.org/uniprot/SMUF1_HUMAN SMUF1_HUMAN] E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA.<ref>PMID:10458166</ref> <ref>PMID:19937093</ref> <ref>PMID:21402695</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Aragon, E]] | + | [[Category: Aragon E]] |
| - | [[Category: Gao, S]] | + | [[Category: Gao S]] |
| - | [[Category: Goerner, N]] | + | [[Category: Goerner N]] |
| - | [[Category: Lopes, T]] | + | [[Category: Lopes T]] |
| - | [[Category: Macias, M J]] | + | [[Category: Macias MJ]] |
| - | [[Category: Massague, J]] | + | [[Category: Massague J]] |
| - | [[Category: Xi, Q]] | + | [[Category: Xi Q]] |
| - | [[Category: Protein binding-peptide complex]]
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| - | [[Category: Smad7]]
| + | |
| - | [[Category: Smurf1]]
| + | |
| - | [[Category: Ww]]
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| Structural highlights
Function
SMUF1_HUMAN E3 ubiquitin-protein ligase that acts as a negative regulator of BMP signaling pathway. Mediates ubiquitination and degradation of SMAD1 and SMAD5, 2 receptor-regulated SMADs specific for the BMP pathway. Promotes ubiquitination and subsequent proteasomal degradation of TRAF family members and RHOA.[1] [2] [3]
Publication Abstract from PubMed
Transforming growth factor (TGF)-beta and BMP signaling is mediated by Smads 1-5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF-beta and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators bind PY motifs and adjacent CDK/MAPK and GSK3 phosphorylation sites in R-Smads in a selective and regulated manner. In contrast, here we show that Smad7 binds YAP, Smurf1, Smurf2, and Nedd4L constitutively, the binding involving a PY motif in Smad7 and no phosphorylation. We also provide a structural basis for how regulators that use WW domain pairs for selective interactions with R-Smads, resort to one single versatile WW domain for binding Smad7 to centralize regulation in the TGF-beta and BMP pathways.
Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-beta Pathways.,Aragon E, Goerner N, Xi Q, Gomes T, Gao S, Massague J, Macias MJ Structure. 2012 Oct 10;20(10):1726-36. doi: 10.1016/j.str.2012.07.014. Epub 2012 , Aug 23. PMID:22921829[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature. 1999 Aug 12;400(6745):687-93. PMID:10458166 doi:10.1038/23293
- ↑ Li S, Lu K, Wang J, An L, Yang G, Chen H, Cui Y, Yin X, Xie P, Xing G, He F, Zhang L. Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem. 2010 May;338(1-2):11-7. doi: 10.1007/s11010-009-0315-y. Epub, 2009 Nov 24. PMID:19937093 doi:10.1007/s11010-009-0315-y
- ↑ Lu K, Li P, Zhang M, Xing G, Li X, Zhou W, Bartlam M, Zhang L, Rao Z, He F. Pivotal role of the C2 domain of the Smurf1 ubiquitin ligase in substrate selection. J Biol Chem. 2011 May 13;286(19):16861-70. Epub 2011 Mar 14. PMID:21402695 doi:10.1074/jbc.M110.211979
- ↑ Aragon E, Goerner N, Xi Q, Gomes T, Gao S, Massague J, Macias MJ. Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-beta Pathways. Structure. 2012 Oct 10;20(10):1726-36. doi: 10.1016/j.str.2012.07.014. Epub 2012 , Aug 23. PMID:22921829 doi:http://dx.doi.org/10.1016/j.str.2012.07.014
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