Structures and mechanisms of circadian rhythms from cyanobacteria to humans

项目摘要 昼夜节律源于基因编码的时钟，这些时钟与外部线索（如光）密切相关， 使生理和行为与24小时太阳活动周期同步。尽管基因网络 到昼夜节律现在已经相对完善，我们仍然不了解许多基本的， 决定这些时钟的24小时基础以及它们如何响应外部时间设置的分子步骤 线索通过将结构生物学和溶液生物物理方法与生物化学和细胞生物学相结合， 旨在确定导致昼夜节律信号的一天时间尺度的基本生物化学原理 并揭示了生物钟忠实地保持内在时间和响应的机制， 对外界线索的反应很强烈在NIGMS之前的资助下，我们研究了哺乳动物和蓝藻的时钟系统， 为了发现不同的时钟蛋白如何组装成调节复合物，并确定蛋白质动力学， 酶活性和/或翻译后修饰影响时钟定时。我们的比较生物化学 这种方法突出了令人惊讶的共同点，例如对互斥结合位点的竞争， 尽管它们的分子结构不同在此，我们将继续努力， 来自不同生物钟的蛋白质组装的结构基础，决定了后 翻译修饰的时钟蛋白质的功能，研究的分子基础夹带的时钟， 外部线索，并寻求新的药物干预的进展。MIRA计划的资金 将为我们提供资源和灵活性，以探索生物学机制的共性， 从蓝细菌到人类的一系列不同物种的计时。

Project Summary Circadian rhythms arise from genetically encoded clocks that are intimately linked to external cues like light to synchronize physiology and behavior with the 24-hour solar cycle. Although the genetic networks that give rise to circadian rhythms are now relatively well established, we still don’t understand many of the fundamental, molecular steps that determine the ~24-hour basis of these clocks and how they respond to external time-setting cues. By integrating structural biology and solution biophysical methods with biochemistry and cell biology, we aim to determine the underlying biochemical principles that lead to the day-long timescale of circadian signaling and uncover the mechanisms that allow biological clocks to faithfully maintain intrinsic timing and respond robustly to external cues. With prior NIGMS funding, we studied clock systems from mammals and cyanobacteria to discover how different clock proteins assemble into regulatory complexes and identified how protein dynamics, enzyme activity and/or post-translational modifications impact clock timing. Our comparative biochemical approach highlighted surprising commonalities, such as the competition for mutually exclusive binding sites, between these clocks despite their different molecular architectures. Here, we will continue to pursue the structural basis of protein assemblies from diverse biological clocks, determine the consequences of post- translational modifications on clock protein function, study the molecular basis for entrainment of clocks to external cues, and seek out new inroads for pharmacological intervention. Funding from the MIRA program would provide us with the resources and flexibility to explore commonalities in mechanisms of biological timekeeping across a diverse array of species from cyanobacteria to humans.