Structures and mechanisms of circadian rhythms from cyanobacteria to humans

项目摘要 昼夜节律产生于基因编码的时钟，这些时钟与外部信号密切相关，比如光到 使生理和行为与24小时太阳周期同步。尽管产生的遗传网络 对于现在比较成熟的昼夜节律，我们仍然不了解许多基本的， 决定这些时钟的~24小时基准以及它们如何响应外部时间设置的分子步骤 暗示。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，我们 目的确定导致昼夜节律信号时间尺度的潜在生化原理。 并揭示使生物钟能够忠实地保持固有的计时和反应的机制 对外部暗示表现出强烈的反应。在之前的NIGMS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控复合体，并确定蛋白质动力学是如何进行的， 酶活性和/或翻译后修饰影响时钟计时。我们的比较生物化学 这种方法突出了令人惊讶的共性，例如相互排斥结合位点的竞争， 在这些时钟之间，尽管它们的分子结构不同。在这里，我们将继续追求 来自不同生物钟的蛋白质组装的结构基础，决定了后 Clock蛋白功能的翻译修饰，研究Clock携带的分子基础 外部线索，并为药物干预寻找新的途径。来自Mira计划的资金 将为我们提供资源和灵活性来探索生物机制中的共性 从蓝藻到人类的各种物种的计时。

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.