An evolutionary hotspot defines functional differences between CRYPTOCHROMES.
An evolutionary hotspot defines functional differences between CRYPTOCHROMES.
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DOI：
10.1038/s41467-018-03503-6
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发表时间：
2018-03-19
影响因子：
16.6
通讯作者：
Green CB
中科院分区：
文献类型：
--
作者：
Rosensweig C;Reynolds KA;Gao P;Laothamatas I;Shan Y;Ranganathan R;Takahashi JS;Green CB
哺乳动物生物钟由转录/翻译反馈环路驱动，该反馈环路由正调节子 (CLOCK/BMAL1) 和阻遏子 (CRYPTOCHROME 1/2 (CRY1/2) 和 PER1/2) 组成。为了了解调控的结构原理，我们使用进化序列分析来识别 CRY/PHL 蛋白家族内的共同进化残基。在这里，我们报告了祖先次级辅因子结合口袋的鉴定，它是抑制性 CRY 中的一个界面，通过与 CLOCK 和 BMAL1 的直接相互作用介导调节。 CLOCK/BMAL1 和 CRY1 之间的结合减弱的突变导致时钟加速，这表明该位点的细微序列分歧可以调节时钟功能。该位点 CRY1 和 CRY2 之间的分歧导致不同的周期性输出。 PER2 的共表达增强了 CRY2 和 CLOCK/BMAL1 在该口袋处的较弱相互作用，表明 PER 表达限制了 CRY2 驱动节律中抑制期的长度。总的来说，这项工作为时钟调节机制的机制和进化变异提供了一个模型。定义生物钟周期性或速率的分子机制尚不清楚。在这里，作者使用多学科方法并确定了一种周期调节机制，该机制取决于核心时钟蛋白彼此的亲和力。
Mammalian circadian clocks are driven by a transcription/translation feedback loop composed of positive regulators (CLOCK/BMAL1) and repressors (CRYPTOCHROME 1/2 (CRY1/2) and PER1/2). To understand the structural principles of regulation, we used evolutionary sequence analysis to identify co-evolving residues within the CRY/PHL protein family. Here we report the identification of an ancestral secondary cofactor-binding pocket as an interface in repressive CRYs, mediating regulation through direct interaction with CLOCK and BMAL1. Mutations weakening binding between CLOCK/BMAL1 and CRY1 lead to acceleration of the clock, suggesting that subtle sequence divergences at this site can modulate clock function. Divergence between CRY1 and CRY2 at this site results in distinct periodic output. Weaker interactions between CRY2 and CLOCK/BMAL1 at this pocket are strengthened by co-expression of PER2, suggesting that PER expression limits the length of the repressive phase in CRY2-driven rhythms. Overall, this work provides a model for the mechanism and evolutionary variation of clock regulatory mechanisms. The molecular mechanisms that define the periodicity or rate of the circadian clock are not well understood. Here the authors use a multidisciplinary approach and identify a mechanism for period regulation that depends on the affinity of the core clock proteins for one another.
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DOI：
10.1073/pnas.1612917113
发表时间：
2016-10-11
影响因子：
11.1
作者：
Chiou, Yi-Ying;Yang, Yanyan;Sancar, Aziz
通讯作者：
Sancar, Aziz
影响因子：
4.8
作者：
Khan, Sanjoy K.;Xu, Haiyan;Liu, Andrew C.
通讯作者：
Liu, Andrew C.
影响因子：
5.3
作者：
Chaves, I;Yagita, K;Tamanini, F
通讯作者：
Tamanini, F
DOI：
10.1126/science.1222804
发表时间：
2012-07-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Huang N;Chelliah Y;Shan Y;Taylor CA;Yoo SH;Partch C;Green CB;Zhang H;Takahashi JS
通讯作者：
Takahashi JS
DOI：
10.1126/science.1257277
发表时间：
2015-01-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Larrondo LF;Olivares-Yañez C;Baker CL;Loros JJ;Dunlap JC
通讯作者：
Dunlap JC