Structural insights into the DNA-binding specificity of E2F family transcription factors.
Structural insights into the DNA-binding specificity of E2F family transcription factors.
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DOI：
10.1038/ncomms10050
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发表时间：
2015-12-03
影响因子：
16.6
通讯作者：
Taipale J
中科院分区：
文献类型：
--
作者：
Morgunova E;Yin Y;Jolma A;Dave K;Schmierer B;Popov A;Eremina N;Nilsson L;Taipale J
哺乳动物细胞周期由转录因子E2F家族控制。典型的E2F与DNA结合为异二聚体，具有相关的二聚化伴侣（DP）蛋白，而非典型的E2F，E2F7和E2F8包含两个DNA结合结构域（DBD）并作为阻遏物。为了理解阻遏的机制，我们已经以原子分辨率解析了E2F8与DNA复合物的结构。我们发现E2F8的第一和第二DBD分别类似于典型的E2F和DP蛋白的DBD。使用分子动力学模拟，生化亲和力测量和染色质免疫沉淀，我们进一步表明，非典型和典型的E2Fs结合相似的DNA序列在体外和体内。我们的研究结果代表了具有两个DBD的E2F蛋白的第一晶体结构，并揭示了非典型E2F可以抑制经典E2F靶基因并对细胞周期进程产生负面影响的机制。 转录因子E2F家族控制着许多重要的细胞过程。在这里，作者确定了含有两个DNA结合结构域的非典型E2F的结构，并提出了这些非典型E2F的作用机制。
The mammalian cell cycle is controlled by the E2F family of transcription factors. Typical E2Fs bind to DNA as heterodimers with the related dimerization partner (DP) proteins, whereas the atypical E2Fs, E2F7 and E2F8 contain two DNA-binding domains (DBDs) and act as repressors. To understand the mechanism of repression, we have resolved the structure of E2F8 in complex with DNA at atomic resolution. We find that the first and second DBDs of E2F8 resemble the DBDs of typical E2F and DP proteins, respectively. Using molecular dynamics simulations, biochemical affinity measurements and chromatin immunoprecipitation, we further show that both atypical and typical E2Fs bind to similar DNA sequences in vitro and in vivo. Our results represent the first crystal structure of an E2F protein with two DBDs, and reveal the mechanism by which atypical E2Fs can repress canonical E2F target genes and exert their negative influence on cell cycle progression. The E2F family of transcription factors controls many important cellular processes. Here, the authors determine the structure of an atypical E2F that contains two DNA binding domains, and propose a mechanism of action for these atypical E2Fs.