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Article: Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers

TitleStructural basis for the cooperative DNA recognition by Smad4 MH1 dimers
Authors
Issue Date2011
Citation
Nucleic Acids Research, 2011, v. 39, n. 18, p. 8213-8222 How to Cite?
AbstractSmad proteins form multimeric complexes consisting of the 'common partner' Smad4 and receptor regulated R-Smads on clustered DNA binding sites. Deciphering how pathway specific Smad complexes multimerize on DNA to regulate gene expression is critical for a better understanding of the cis-regulatory logic of TGF-β and BMP signaling. To this end, we solved the crystal structure of the dimeric Smad4 MH1 domain bound to a palindromic Smad binding element. Surprisingly, the Smad4 MH1 forms a constitutive dimer on the SBE DNA without exhibiting any direct protein-protein interactions suggesting a DNA mediated indirect readout mechanism. However, the R-Smads Smad1, Smad2 and Smad3 homodimerize with substantially decreased efficiency despite pronounced structural similarities to Smad4. Therefore, intricate variations in the DNA structure induced by different Smads and/or variant energetic profiles likely contribute to their propensity to dimerize on DNA. Indeed, competitive binding assays revealed that the Smad4/R-Smad heterodimers predominate under equilibrium conditions while R-Smad homodimers are least favored. Together, we present the structural basis for DNA recognition by Smad4 and demonstrate that Smad4 constitutively homo-and heterodimerizes on DNA in contrast to its R-Smad partner proteins by a mechanism independent of direct protein contacts. © 2011 The Author(s).
Persistent Identifierhttp://hdl.handle.net/10722/253146
ISSN
2020 Impact Factor: 16.971
2020 SCImago Journal Rankings: 9.008
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorBaburajendran, Nithya-
dc.contributor.authorJauch, Ralf-
dc.contributor.authorTan, Clara Yueh Zhen-
dc.contributor.authorNarasimhan, Kamesh-
dc.contributor.authorKolatkar, Prasanna R.-
dc.date.accessioned2018-05-11T05:38:43Z-
dc.date.available2018-05-11T05:38:43Z-
dc.date.issued2011-
dc.identifier.citationNucleic Acids Research, 2011, v. 39, n. 18, p. 8213-8222-
dc.identifier.issn0305-1048-
dc.identifier.urihttp://hdl.handle.net/10722/253146-
dc.description.abstractSmad proteins form multimeric complexes consisting of the 'common partner' Smad4 and receptor regulated R-Smads on clustered DNA binding sites. Deciphering how pathway specific Smad complexes multimerize on DNA to regulate gene expression is critical for a better understanding of the cis-regulatory logic of TGF-β and BMP signaling. To this end, we solved the crystal structure of the dimeric Smad4 MH1 domain bound to a palindromic Smad binding element. Surprisingly, the Smad4 MH1 forms a constitutive dimer on the SBE DNA without exhibiting any direct protein-protein interactions suggesting a DNA mediated indirect readout mechanism. However, the R-Smads Smad1, Smad2 and Smad3 homodimerize with substantially decreased efficiency despite pronounced structural similarities to Smad4. Therefore, intricate variations in the DNA structure induced by different Smads and/or variant energetic profiles likely contribute to their propensity to dimerize on DNA. Indeed, competitive binding assays revealed that the Smad4/R-Smad heterodimers predominate under equilibrium conditions while R-Smad homodimers are least favored. Together, we present the structural basis for DNA recognition by Smad4 and demonstrate that Smad4 constitutively homo-and heterodimerizes on DNA in contrast to its R-Smad partner proteins by a mechanism independent of direct protein contacts. © 2011 The Author(s).-
dc.languageeng-
dc.relation.ispartofNucleic Acids Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleStructural basis for the cooperative DNA recognition by Smad4 MH1 dimers-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1093/nar/gkr500-
dc.identifier.pmid21724602-
dc.identifier.scopuseid_2-s2.0-80054063198-
dc.identifier.volume39-
dc.identifier.issue18-
dc.identifier.spage8213-
dc.identifier.epage8222-
dc.identifier.eissn1362-4962-
dc.identifier.isiWOS:000295687700034-
dc.identifier.issnl0305-1048-

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