Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers.
Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers.
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DOI：
10.1093/nar/gkr500
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发表时间：
2011-10
影响因子：
14.9
通讯作者：
Kolatkar PR
中科院分区：
文献类型：
--
作者：
Baburajendran N;Jauch R;Tan CY;Narasimhan K;Kolatkar PR
Smad蛋白形成由“共同伴侣”Smad 4和受体调节的R-Smads在成簇的DNA结合位点上组成的多聚体复合物。解读途径特异性Smad复合物如何在DNA上多聚化以调节基因表达对于更好地理解TGF-β和BMP信号传导的顺式调节逻辑至关重要。为此，我们解决了二聚体的Smad 4 MH 1结构域结合到回文的Smad结合元件的晶体结构。令人惊讶的是，Smad 4 MH 1在SBE DNA上形成组成型二聚体，而没有表现出任何直接的蛋白质-蛋白质相互作用，这表明DNA介导的间接读出机制。然而，R-Smads Smad 1，Smad 2和Smad 3同源二聚化的效率大大降低，尽管明显的结构相似性Smad 4。因此，由不同的Smads和/或变体能量分布诱导的DNA结构的复杂变化可能有助于它们在DNA上二聚化的倾向。事实上，竞争性结合试验表明，Smad 4/R-Smad异源二聚体在平衡条件下占主导地位，而R-Smad同源二聚体最不受欢迎。总之，我们提出的结构基础的DNA识别Smad 4和证明，Smad 4组成型同源和异源二聚体的DNA上的R-Smad伴侣蛋白的一种机制，独立于直接的蛋白质接触。
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.
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影响因子：
4.8
作者：
Chai, JJ;Wu, JW;Shi, YG
通讯作者：
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DOI：
10.1107/s0907444904019158
发表时间：
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影响因子：
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通讯作者：
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