Structural basis for the Smad5 MH1 domain to recognize different DNA sequences.
Structural basis for the Smad5 MH1 domain to recognize different DNA sequences.
复制标题
Smad5 MH1 结构域识别不同 DNA 序列的结构基础。
DOI：
10.1093/nar/gkv848
复制
发表时间：
2015-10-15
影响因子：
14.9
通讯作者：
Wu JW
中科院分区：
文献类型：
--
作者：
Chai N;Li WX;Wang J;Wang ZX;Yang SM;Wu JW
Smad 蛋白是 TGF-β 信号传导的重要细胞内介质，可将信号直接从细胞表面受体传递至细胞核。 Smad 的 MH1 结构域在 DNA 识别中发挥着关键作用。两种类型的 DNA 序列被鉴定为 Smad 结合基序：Smad 结合元件 (SBE) 和富含 GC 的序列。在这里，我们报告了与富含 GC 的序列复合的 Smad5 MH1 结构域的第一个晶体结构。与Smad5-MH1/SBE复合体结构相比，Smad5 MH1结构域通过相同的β-发夹接触GC富含位点，但具体的相互作用方式不同。保守的 β-发夹残基与最小的富含 GC 的位点 5'-GGC-3' 进行碱基特异性接触。 Smad5-MH1 在富含 GC 的 DNA 上的组装也会导致明显的 DNA 构象变化。此外，Smad5-MH1与复合DNA序列复合的晶体结构表明，MH1结构域以模块化结合模式靶向每个结合位点（富含GC或SBE），并且DNA间隔区的长度影响MH1组装。总之，我们的工作为 Smad MH1 结构域与 DNA 靶标的识别和结合特异性提供了结构基础。
Smad proteins are important intracellular mediators of TGF-β signalling, which transmit signals directly from cell surface receptors to the nucleus. The MH1 domain of Smad plays a key role in DNA recognition. Two types of DNA sequence were identified as Smad binding motifs: the Smad binding element (SBE) and the GC-rich sequence. Here we report the first crystal structure of the Smad5 MH1 domain in complex with the GC-rich sequence. Compared with the Smad5-MH1/SBE complex structure, the Smad5 MH1 domain contacts the GC-rich site with the same β-hairpin, but the detailed interaction modes are different. Conserved β-hairpin residues make base specific contacts with the minimal GC-rich site, 5′-GGC-3′. The assembly of Smad5-MH1 on the GC-rich DNA also results in distinct DNA conformational changes. Moreover, the crystal structure of Smad5-MH1 in complex with a composite DNA sequence demonstrates that the MH1 domain is targeted to each binding site (GC-rich or SBE) with modular binding modes, and the length of the DNA spacer affects the MH1 assembly. In conclusion, our work provides the structural basis for the recognition and binding specificity of the Smad MH1 domain with the DNA targets.