Structure and Function of Circadian Clock Light Sensors

昼夜节律时钟光传感器的结构和功能

• 批准号: 7633268
• 负责人: BRIAN R CRANE
• 金额: $ 28.4万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633268
• 关键词: Affect; Behavior; Behavior Therapy; Biochemical; Biochemistry; Biological; Biological Clocks; Biological Models; Biology; Cells; Cellular Assay; Cellular biology; Chemicals; Chemistry; Clock protein; Complex; Couples; Crystallography; Development; Disease; Drosophila genus; Drosophila melanogaster; Environment; Feedback; Flavins; Genes; Genetic; Human; In Vitro; Individual; Investigation; Length; Light; Link; Mental disorders; Metabolism; Molds; Molecular; Neurospora; Neurospora crassa; Optics; Organism; Oxidation-Reduction; Pathway interactions; Peripheral; Photochemistry; Photoreceptors; Physiologic pulse; Physiology; Play; Process; Property; Proteins; Research Personnel; Resolution; Role; Signal Transduction; Solutions; Spectrum Analysis; Spin Labels; Stream; Structure; System; Tertiary Protein Structure; Testing; Time; Variant; circadian pacemaker; cofactor; computerized data processing; cryptochrome; design; fly; fungus; in vivo; mutant; protein complex; protein protein interaction; protein structure; response; sensor; transcription factor; white collar 1

DESCRIPTION (provided by applicant): Organisms have developed complex regulatory systems in order to couple metabolism and cell development with changes in their environment. Such adaptation is well demonstrated by circadian clocks, which synchronize cellular responses to the diurnal light cycle. Due to their central role in pacing metabolism, biological clocks impact many aspects of human physiology, behavior and the treatment of disease. Although genetics and cell biology have made great progress in understanding the function of clock genes, the molecular mechanisms that compose the underlying transcriptional feedback loops, and their light entrapment, remain largely unknown. Primary photoreceptors and their targets have been identified in eukaryotic model systems such as Neurospora, (filamentous fungi) and Drosophila (flies). Preliminary characterization of light-sensors white collar 1 (WC-1) and vivid (WD) from Neurospora and cryptochrome (CRY) from Drosophila, has defined structures and reactivities that implicate both flavin photochemistry and thiolate redox chemistry in the activation of Per-Arnt-Sim (PAS) domain-containing transcription factors. Crystallographic and spectroscopic characterization of how large-scale protein conformational changes propagate from cofactor photochemistry to generate complex alterations in protein/protein interactions will provide a molecular understanding for clock function. Studies of circadian clock proteins have been hampered by the complexity of the cellular responses, the presence of multiple entrainment mechanisms, and the lack of structures for key proteins. High-resolution structures of these photoreceptors in various states of activation and in complex with their downstream partners will delineate individual residues important for cellular reactivity. Both in vivo and in vitro analysis of variant clock proteins designed to decouple their properties will help fragment entrainment pathways and identify additional levels of clock control, such as response to cellular redox potentials. Parallel investigations of related mammalian clock proteins will reveal mechanisms of action that will aid in the prediction and perturbation of function. Ultimately, such studies of clock proteins will provide a molecular description of behavior that promises advancements in the treatment of mental disorders and many other maladies.

描述（由申请人提供）：生物已经开发了复杂的调节系统，以使代谢和细胞发育与环境变化息息。这种适应性通过昼夜节律很好地证明了这一点，这同步了细胞对昼夜光周期的反应。由于它们在起搏代谢中的核心作用，生物钟会影响人类生理学，行为和疾病治疗的许多方面。尽管遗传学和细胞生物学在理解时钟基因的功能方面取得了长足的进步，但构成基本转录反馈回路的分子机制及其光夹带仍然很少知道。在真核模型系统（例如Neurospora，（丝状真菌）和果蝇）（FLIES）等真核模型系统中已经确定了原发性光感受器及其靶标。来自Neurospora的白领1（WC-1）和Vivid（WD）的初步表征，来自果蝇的神经孢子和加密色素（Cry）（cry）定义了结构和重复性，这既暗示了Flavin光化学和硫代硫代氧化物氧化还原化学在per-Arnt-sim（PAS）激活中的转录（PAS）domain domain-domain-domain-domain-domain-Contription cromentsription。大规模蛋白质构象变化如何从辅因子光化学传播到蛋白质/蛋白质相互作用的复杂变化将为时钟功能提供分子理解，从而对时钟功能产生了复杂的变化。昼夜节律蛋白的研究受到细胞反应的复杂性，多种夹带机制的存在以及关键蛋白质缺乏结构的影响。这些光感受器在各种激活状态和其下游伴侣中的高分辨率结构将描绘出对细胞反应性很重要的个体残基。体内和体外分析旨在解脱其性质的变异时钟蛋白都将有助于碎片夹带途径并确定其他时钟控制的水平，例如对细胞氧化还原电位的响应。对相关哺乳动物时钟蛋白的并行研究将揭示作用机制，这将有助于预测和扰动功能。最终，这种对时钟蛋白的研究将提供对行为的分子描述，该行为有望在治疗精神障碍和许多其他疾病方面的进步。