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Science:哺乳昼夜节律钟蛋白结构信息被破解

来源:生物谷 2012-06-04 22:21

哺乳动物的昼夜节律,是由以约24小时为周期的自我调控转录反馈机制掌控的。该机制的关键组分是一个异二聚化转录活化因子,包含两个bHLH-PAS结构域蛋白亚基:CLOCK和BMAL1。

5月31日Science杂志在线发表了Nian Huang等的研究论文,以2.3埃米的分辨率解析了包含小鼠CLOCK:BMAL1 bHLH-PAS结构域的蛋白晶体复合物的结构生物学信息。

该研究表明,在CLOCK和BMAL1 两个亚基中的三个结构域间均存在一个不同寻常的非对称异二聚体。bHLH,PAS-A 和PAS-B紧密缠绕,参与二聚化相互作用,产生三个不同的蛋白界面。破坏此异二聚体界面的突变,可影响CLOCK:BMAL1复合物的稳定性和活力,以及昼夜节律周期性。CLOCK:BMAL1复合物结构的解析为从原子水平理解哺乳动物昼夜节律钟的驱动机制创造了良好的开端。(生物谷bioon.com)

Crystal Structure of the Heterodimeric CLOCK:BMAL1 Transcriptional Activator Complex

Nian Huang, Yogarany Chelliah, Yongli Shan, et al.

The circadian clock in mammals is driven by an autoregulatory transcriptional feedback mechanism that takes about 24 hours to complete. A key component of this mechanism is a heterodimeric transcriptional activator consisting of two bHLH-PAS domain protein subunits, CLOCK and BMAL1. Here, we report the crystal structure of a complex containing the mouse CLOCK:BMAL1 bHLH-PAS domains at 2.3 ? resolution. The structure reveals an unusual asymmetric heterodimer with the three domains in each of the two subunits, bHLH, PAS-A and PAS-B tightly intertwined and involved in dimerization interactions, resulting in three distinct protein interfaces. Mutations that perturb the observed heterodimer interfaces affect the stability and activity of the CLOCK:BMAL1 complex as well as the periodicity of the circadian oscillator. The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock.

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