Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers

Nithya Baburajendran, Ralf Jauch, Clara Yueh Zhen Tan, Kamesh Narasimhan, Prasanna Kolatkar

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Smad 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.

Original languageEnglish
Pages (from-to)8213-8222
Number of pages10
JournalNucleic Acids Research
Volume39
Issue number18
DOIs
Publication statusPublished - 1 Oct 2011
Externally publishedYes

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DNA
Receptor-Regulated Smad Proteins
Smad Proteins
Proteins
Competitive Binding
Binding Sites
Gene Expression

ASJC Scopus subject areas

  • Genetics

Cite this

Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers. / Baburajendran, Nithya; Jauch, Ralf; Tan, Clara Yueh Zhen; Narasimhan, Kamesh; Kolatkar, Prasanna.

In: Nucleic Acids Research, Vol. 39, No. 18, 01.10.2011, p. 8213-8222.

Research output: Contribution to journalArticle

Baburajendran, N, Jauch, R, Tan, CYZ, Narasimhan, K & Kolatkar, P 2011, 'Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers', Nucleic Acids Research, vol. 39, no. 18, pp. 8213-8222. https://doi.org/10.1093/nar/gkr500
Baburajendran, Nithya ; Jauch, Ralf ; Tan, Clara Yueh Zhen ; Narasimhan, Kamesh ; Kolatkar, Prasanna. / Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers. In: Nucleic Acids Research. 2011 ; Vol. 39, No. 18. pp. 8213-8222.
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