Structural Insights into the CRTC2-CREB Complex Assembly on CRE
Structural Insights into the CRTC2-CREB Complex Assembly on CRE
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DOI：
10.1016/j.jmb.2018.04.038
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发表时间：
2018-06-22
影响因子：
5.6
通讯作者：
Xiang, Song
中科院分区：
文献类型：
--
作者：
Song, Yihui;Zhai, Liting;Xiang, Song
CAMP反应元件(CAMP)反应元件(CRE)结合蛋白(CREB)在cAMP的转录调控中起核心作用，而CREB调节的转录共激活因子(CRTC)在CREB介导的转录激活中起关键作用。在刺激下，CRTCs移位到细胞核内，并与CRE启动子上的CREB形成复合体，激活靶基因转录。它们在能量平衡、长期记忆、长寿和其他过程中的作用，突显了它们的生理重要性。CRTC上的CREB结合域已经被定位，它与CREB碱性亮氨酸拉链结构域相互作用，该结构域也介导与含有CRE的DNA的相互作用。我们报道了一个包含CRTC2 CREB结合域、CREB碱性亮氨酸拉链结构域和一个含有CRE的DNA的复合体的晶体结构。结构分析表明，CRTC和CREB在含CRE的DNA上形成2：2的复合体，CRTC通过高度保守的残基与CREB和DNA相互作用。结构导向的功能研究表明，这两种相互作用对于复杂的组装和CREB在DNA上的稳定都是至关重要的。有趣的是，我们发现CRTC DNA的相互作用赋予了对固有DNA形状的选择性，这可能在Cre基因的选择性转录激活中发挥作用。(C)爱思唯尔有限公司出版的2018年。
The cAMP response element (CRE) binding protein (CREB) is central in the transcription regulation by cAMP, and the CREB-regulated transcriptional coactivators (CRTCs) play critical roles in CREB-mediated transcription activation. Upon stimulation, CRTCs translocate into the nucleus and complex with CREB on CRE promoters to activate target gene transcription. Their physiological importance is underscored by their function in energy balance, long-term memory, longevity and other processes. The CREB binding domain on CRTCs has been mapped, which interacts with the CREB basic leucine zipper domain that also mediates interaction with CRE-containing DNA. We report here crystal structures of a complex containing the CRTC2 CREB binding domain, the CREB basic leucine zipper domain and a CRE-containing DNA. The structures revealed that CRTC and CREB form a 2:2 complex on CRE-containing DNA, and CRTC interacts with both CREB and DNA through highly conserved residues. Structure-guided functional studies revealed that both interactions are crucial for the complex assembly and CREB stabilization on DNA. Interestingly, we found that the CRTC DNA interaction confers selectivity toward the intrinsic DNA shape, which may play a role in selective transcription activation of the CRE genes. (C) 2018 Published by Elsevier Ltd.