The circadian circuit, a roughly 24 h molecular feedback loop, or clock, is conserved from bacteria to animals and allows for enhanced organismal survival by facilitating the anticipation of the day/night cycle. With circadian regulation reportedly impacting as high as 80% of protein coding genes in higher eukaryotes, the protein-based circadian clock broadly regulates physiology and behavior. Due to the extensive interconnection between the clock and other cellular systems, chronic disruption of these molecular rhythms leads to a decrease in organismal fitness as well as an increase of disease rates in humans. Importantly, recent research has demonstrated that proteins comprising the circadian clock network display a significant amount of intrinsic disorder. In this work, we focus on the extent of intrinsic disorder in the circadian clock and its potential mechanistic role in circadian timing. We highlight the conservation of disorder by quantifying the extent of computationally-predicted protein disorder in the core clock of the key eukaryotic circadian model organisms Drosophila melanogaster, Neurospora crassa, and Mus musculus. We further examine previously published work, as well as feature novel experimental evidence, demonstrating that the core negative arm circadian period drivers FREQUENCY (Neurospora crassa) and PERIOD-2 (PER2) (Mus musculus), possess biochemical characteristics of intrinsically disordered proteins. Finally, we discuss the potential contributions of the inherent biophysical principals of intrinsically disordered proteins that may explain the vital mechanistic roles they play in the clock to drive their broad evolutionary conservation in circadian timekeeping. The pervasive conservation of disorder amongst the clock in the crown eukaryotes suggests that disorder is essential for optimal circadian timing from fungi to animals, providing vital homeostatic cellular maintenance and coordinating organismal physiology across phylogenetic kingdoms.

中文翻译：

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内在紊乱是保守昼夜节律回路中各组成部分的一个基本特征

昼夜节律回路是一个大约 24 小时的分子反馈回路或时钟，从细菌到动物都是保守的，并通过促进昼夜周期的预期来提高生物体的存活率。据报道，昼夜节律调节影响高等真核生物中高达 80% 的蛋白质编码基因，因此基于蛋白质的生物钟广泛调节生理和行为。由于生物钟和其他细胞系统之间存在广泛的相互联系，这些分子节律的长期破坏会导致人体健康状况的下降以及人类患病率的增加。重要的是，最近的研究表明，构成生物钟网络的蛋白质表现出大量的内在紊乱。在这项工作中，我们重点关注生物钟内在紊乱的程度及其在昼夜节律计时中的潜在机制作用。我们通过量化关键真核昼夜节律模型生物果蝇、粗糙脉孢菌和小家鼠的核心时钟中计算预测的蛋白质紊乱的程度来强调紊乱的保守性。我们进一步研究了之前发表的工作以及新颖的实验证据，证明核心负臂昼夜节律驱动因子 FREQUENCY（粗糙脉孢菌）和 PERIOD-2 (PER2)（小家鼠）具有本质上无序蛋白质的生化特征。最后，我们讨论了本质无序蛋白质的固有生物物理原理的潜在贡献，这可能解释它们在生物钟中所发挥的重要机制作用，以驱动其在昼夜节律计时中广泛的进化保守性。冠真核生物时钟中普遍存在的紊乱现象表明，紊乱对于从真菌到动物的最佳昼夜节律至关重要，提供重要的细胞稳态维持并协调整个系统发育界的生物生理学。