Structure of a Biologically Active Estrogen Receptor-Coactivator Complex on DNA
Structure of a Biologically Active Estrogen Receptor-Coactivator Complex on DNA
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DOI：
10.1016/j.molcel.2015.01.025
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发表时间：
2015-03-19
期刊：
影响因子：
16
通讯作者：
O'Malley, Bert W.
中科院分区：
文献类型：
--
作者：
Yi, Ping;Wang, Zhao;O'Malley, Bert W.
雌激素受体 (ER/ESR1) 是一种对发育、生殖、代谢和癌症至关重要的转录因子。 ER 功能取决于其募集初级和次级共激活剂的能力，但缺乏全长受体-共激活剂复合物的结构信息来补充先前存在的、有时有争议的生化信息。在这里，我们使用冷冻电子显微镜 (cryo-EM) 来确定 DNA 结合的 ER α、类固醇受体辅激活剂 3 (SRC-3/NCOA3) 和次级辅激活剂 (p300/EP300) 的活性复合物的四级结构。我们的结构模型表明该复合物具有以下组装机制：两个配体结合的 ER α 单体中的每一个都通过 ER α 的反式激活结构域独立招募一个 SRC-3 蛋白；两个 SRC-3 通过多次接触依次与一种 p300 蛋白的不同区域结合。我们还提供了激活功能 1 (AF-1) 在全长核受体中定位的结构证据，这支持了 AF-1 在 SRC-3 招募中的作用。
Estrogen receptor (ER/ESR1) is a transcription factor critical for development, reproduction, metabolism, and cancer. ER function hinges on its ability to recruit primary and secondary coactivators, yet structural information on the full-length receptor-coactivator complex to complement preexisting and sometimes controversial biochemical information is lacking. Here, we use cryoelectron microscopy (cryo-EM) to determine the quaternary structure of an active complex of DNA-bound ER alpha, steroid receptor coactivator 3 (SRC-3/NCOA3), and a secondary coactivator (p300/EP300). Our structural model suggests the following assembly mechanism for the complex: each of the two ligand-bound ER alpha monomers independently recruits one SRC-3 protein via the transactivation domain of ER alpha; the two SRC-3s in turn bind to different regions of one p300 protein through multiple contacts. We also present structural evidence for the location of activation function 1 (AF-1) in a full-length nuclear receptor, which supports a role for AF-1 in SRC-3 recruitment.