This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

2djy

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 04:00, 10 September 2015

Solution structure of Smurf2 WW3 domain-Smad7 PY peptide complex

Structural highlights

2djy is a 2 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	SMURF2 (HUMAN), SMAD7, MADH7, MADH8 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[SMAD7_HUMAN] Genetic variations in SMAD7 influence susceptibility to colorectal cancer type 3 (CRCS3) [MIM: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.^[1]

Function

[SMUF2_HUMAN] 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.^[2] ^[3] [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).^[4] ^[5] ^[6] ^[7] ^[8]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Smurf2 is an E3 ubiquitin ligase that drives degradation of the transforming growth factor-beta receptors and other targets. Recognition of the receptors by Smurf2 is accomplished through an intermediary protein, Smad7. Here we have demonstrated that the WW3 domain of Smurf2 can directly bind to the Smad7 polyproline-tyrosine (PY) motif. Of particular interest, the highly conserved WW domain binding site Trp, which interacts with target PY motifs, is a Phe in the Smurf2 WW3 domain. To examine this interaction, the solution structure of the complex between the Smad7 PY motif region (ELESPPPPYSRYPMD) and the Smurf2 WW3 domain was determined. The structure reveals that, in addition to binding the PY motif, the WW3 domain binds six residues C-terminal to the PY motif (PY-tail). Although the Phe in the WW3 domain binding site decreases affinity relative to the canonical Trp, this is balanced by additional interactions between the PY-tail and the beta1-strand and beta1-beta2 loop of the WW3 domain. The interaction between the Smurf2 WW3 domain and the Smad7 PY motif is the first example of PY motif recognition by a WW domain with a Phe substituted for the binding site Trp. This unusual interaction allows the Smurf2 WW3 domain to recognize a subset of PY motif-containing proteins utilizing an expanded surface to provide specificity.

An expanded WW domain recognition motif revealed by the interaction between Smad7 and the E3 ubiquitin ligase Smurf2.,Chong PA, Lin H, Wrana JL, Forman-Kay JD J Biol Chem. 2006 Jun 23;281(25):17069-75. Epub 2006 Apr 26. PMID:16641086^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Broderick P, Carvajal-Carmona L, Pittman AM, Webb E, Howarth K, Rowan A, Lubbe S, Spain S, Sullivan K, Fielding S, Jaeger E, Vijayakrishnan J, Kemp Z, Gorman M, Chandler I, Papaemmanuil E, Penegar S, Wood W, Sellick G, Qureshi M, Teixeira A, Domingo E, Barclay E, Martin L, Sieber O, Kerr D, Gray R, Peto J, Cazier JB, Tomlinson I, Houlston RS. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007 Nov;39(11):1315-7. Epub 2007 Oct 14. PMID:17934461 doi:ng.2007.18
↑ Bonni S, Wang HR, Causing CG, Kavsak P, Stroschein SL, Luo K, Wrana JL. TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol. 2001 Jun;3(6):587-95. PMID:11389444 doi:10.1038/35078562
↑ Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL. Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol. 2003 May;5(5):410-21. PMID:12717440 doi:10.1038/ncb975
↑ Lebrun JJ, Takabe K, Chen Y, Vale W. Roles of pathway-specific and inhibitory Smads in activin receptor signaling. Mol Endocrinol. 1999 Jan;13(1):15-23. PMID:9892009
↑ Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell. 2000 Dec;6(6):1365-75. PMID:11163210
↑ Liu X, Nagarajan RP, Vale W, Chen Y. Phosphorylation regulation of the interaction between Smad7 and activin type I receptor. FEBS Lett. 2002 May 22;519(1-3):93-8. PMID:12023024
↑ Shi W, Sun C, He B, Xiong W, Shi X, Yao D, Cao X. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol. 2004 Jan 19;164(2):291-300. Epub 2004 Jan 12. PMID:14718519 doi:10.1083/jcb.200307151
↑ Seong HA, Jung H, Kim KT, Ha H. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins. J Biol Chem. 2007 Apr 20;282(16):12272-89. Epub 2007 Feb 27. PMID:17327236 doi:10.1074/jbc.M609279200
↑ Chong PA, Lin H, Wrana JL, Forman-Kay JD. An expanded WW domain recognition motif revealed by the interaction between Smad7 and the E3 ubiquitin ligase Smurf2. J Biol Chem. 2006 Jun 23;281(25):17069-75. Epub 2006 Apr 26. PMID:16641086 doi:10.1074/jbc.M601493200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2djy"

@@ Line 2: / Line 2: @@
 <StructureSection load='2djy' size='340' side='right' caption='[[2djy]], [[NMR_Ensembles_of_Models | 30 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2djy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2DJY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2DJY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2djy]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2DJY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2DJY FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMURF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), SMAD7, MADH7, MADH8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMURF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SMAD7, MADH7, MADH8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2djy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2djy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2djy RCSB], [http://www.ebi.ac.uk/pdbsum/2djy PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2djy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2djy OCA], [http://pdbe.org/2djy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2djy RCSB], [http://www.ebi.ac.uk/pdbsum/2djy PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 28: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2djy" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Chong, P A]]
 [[Category: Forman-Kay, J D]]

2djy

From Proteopedia

Revision as of 04:00, 10 September 2015

Solution structure of Smurf2 WW3 domain-Smad7 PY peptide complex

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox