Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains
Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains
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DOI：
10.1038/emboj.2009.30
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发表时间：
2009-04-08
期刊：
影响因子：
11.4
通讯作者：
Wright, Peter E.
中科院分区：
文献类型：
--
作者：
Wojciak, Jonathan M.;Martinez-Yamout, Maria A.;Wright, Peter E.
CBP/p300转录辅激活因子通过与多种转录因子相互作用整合细胞信号来介导基因表达。为了阐明CBP依赖性基因表达的分子和结构基础，我们分别确定了CBP TAZ 1和TAZ 2结构域与信号转导子和转录激活子2（STAT 2）和STAT 1的反式激活结构域（TADs）的复合结构。尽管TAZ 1和TAZ 2结构域的拓扑相似性，螺旋包装和表面凹槽的细微差异构成目标选择性的主要决定因素。我们的研究结果表明，TAZ 1优先结合能够同时接触多个表面凹槽的长TAD，而较小的TAD仅限于一个连续的结合表面与TAZ 2形成复合物。两种STAT TAD的复合物形成涉及偶联折叠和结合，由分子间疏水和静电相互作用驱动。磷酸化的S727，所需的最大转录活性的STAT 1，不增强任何CBP结构域的结合。由于不同的STAT TADs识别CBP/p300的不同区域，因此STAT异二聚体有可能进行多价结合，从而增强共激活因子向启动子的募集。
CBP/p300 transcriptional coactivators mediate gene expression by integrating cellular signals through interactions with multiple transcription factors. To elucidate the molecular and structural basis for CBP-dependent gene expression, we determined structures of the CBP TAZ1 and TAZ2 domains in complex with the transactivation domains (TADs) of signal transducer and activator of transcription 2 (STAT2) and STAT1, respectively. Despite the topological similarity of the TAZ1 and TAZ2 domains, subtle differences in helix packing and surface grooves constitute major determinants of target selectivity. Our results suggest that TAZ1 preferentially binds long TADs capable of contacting multiple surface grooves simultaneously, whereas smaller TADs that are restricted to a single contiguous binding surface form complexes with TAZ2. Complex formation for both STAT TADs involves coupled folding and binding, driven by intermolecular hydrophobic and electrostatic interactions. Phosphorylation of S727, required for maximal transcriptional activity of STAT1, does not enhance binding to any of the CBP domains. Because the different STAT TADs recognize different regions of CBP/p300, there is a potential for multivalent binding by STAT heterodimers that could enhance the recruitment of the coactivators to promoters.