| First Author | Baburajendran N | Year | 2011 |
| Journal | Nucleic Acids Res | Volume | 39 |
| Issue | 18 | Pages | 8213-22 |
| PubMed ID | 21724602 | Mgi Jnum | J:183041 |
| Mgi Id | MGI:5317378 | Doi | 10.1093/nar/gkr500 |
| Citation | Baburajendran N, et al. (2011) Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers. Nucleic Acids Res 39(18):8213-22 |
| abstractText | 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-beta 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. |
