Structural Flexibility Mediates Circadian Adaptation in Diverse Organisms

结构灵活性介导多种生物体的昼夜节律适应

基本信息

批准号：
10291972
负责人：
Brian David Zoltowski
金额：
$ 42.56万
依托单位：
SOUTHERN METHODIST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291972
关键词：
ARNT gene Affinity Allosteric Regulation Animals BLR1 gene Binding Biochemical Bioinformatics Biological Biological Assay Biology Biophysics C-terminal Cell model Chemical Structure Chemicals Chemistry Clock protein Complex Computing Methodologies Coupled Coupling Crystallography Cues Data Diabetes Mellitus Disease Drug Targeting Elements Environment Family Feedback Funding Genetic Genetic Transcription Hour Light Malignant Neoplasms Mammals Mediating Methodology Methods Modeling Molecular Molecular Conformation Motivation Mus Organism Oxygen Pathway interactions Photoreceptors Physiology Plants Process Protein Dynamics Protein Family Protein Isoforms Proteins Regulation Research Personnel Rock Pigeons Role Scaffolding Protein Sensory Signal Transduction Site Solvents Stimulus Structure Surface System Tail Tertiary Protein Structure Therapeutic Time Translations base biophysical analysis biophysical techniques chemical genetics circadian circadian pacemaker cofactor computer studies cryptochrome design dimer fitness flexibility functional plasticity fungus human disease improved in vivo light effects member optogenetics photoperiodicity plant fungi protein function protein protein interaction response small molecule tool transcription factor undergraduate student voltage

项目摘要

Project Summary: Circadian clocks have evolved to synchronize organism physiology with environmental conditions. Central to their function is the ability to adapt to unique environmental niches to maintain a 24-hour daily cycle to optimize organism fitness. Although circadian networks differ in various organisms, two hallmarks of circadian networks are conserved across phyla: 1) A central oscillator composed of a transcription-translation feedback loop (TTFL), and 2) Sensory elements that entrain the TTFL to endogenous and environmental cues. Examination of circadian network topology across diverse organisms reveals two protein domain families are widely employed to integrate environmental stimuli into circadian networks. These are members of the Light-Oxygen-Voltage (LOV: fungi and plants) and Cryptochromes (CRY: plants and animals). Results in diverse organisms demonstrate that despite conservation, the mechanisms and roles of these proteins can differ considerably. How LOV and CRY proteins are able to adapt the magnitude and mode of signal propagation to adapt to environmental conditions is unknown. Based on recent computational and biophysical studies of LOV and CRY systems in plants, fungi, and animals, we hypothesize that LOV/CRY systems leverage a dynamic conformational landscape to enable integration of environmental variables that are species and/or environment specific. By understanding these complex landscapes, we can: 1) Predict how closely related organisms tune circadian responses to maximize fitness. 2) Develop strategies to manipulate organism physiology to rectify either deleterious (disease causing) errors or encourage beneficial adaptations. Herein, we develop a platform, amendable to undergraduate researchers, that integrates biological, biophysical, and computational approaches. We focus on two aims to verify plasticity in circadian networks. We specifically focus on systems that retain allosteric mechanisms analogous to those found in mammals, thereby allowing us to develop new strategies to impact human disease. Aim 1: Leveraging recent computational and structural data we will directly evaluate allosteric switch residues that alter the conformational landscape of LOV proteins. Specific focus will be on residues allowing closely related plant and fungal species to alter signaling dynamics in an environmentally specific manner. We will demonstrate tunability of these signaling networks, thereby developing new methodologies to manipulate organism physiology. Aim 2: Leveraging recent chemical and structural studies of a photoactive vertebrate CRY, we will demonstrate that analogous structural plasticity exists in CRY-based systems allowing organisms to alter the magnitude and direction of conformational responses. Using structural and biochemical approaches we will develop an optogenetic tool capable of manipulating mammalian circadian networks. The combined approach enables us to identify natural mechanisms employed to tune circadian networks, thereby allowing the design of new genetic and chemical mechanisms to manipulate organism fitness.

项目摘要：昼夜节律钟已经演变为将生物生理与环境条件同步。中心它们的功能是能够适应独特的环境领域以保持每日24小时的周期以优化有机体健身。尽管昼夜节律在各种生物中有所不同，但两个昼夜节网络的标志在门上保守：1）由转录翻译反馈循环（TTFL）组成的中心振荡器， 2）将TTFL夹在内源性和环境线索中的感觉元素。检查昼夜节律跨不同生物的网络拓扑揭示了两个蛋白质领域家族被广泛用于整合环境刺激进入昼夜节律网络。这些是光线电压的成员（Lov：真菌和植物）和隐性（哭泣：植物和动物）。导致多种生物表明，尽管保护，这些蛋白质的机制和作用可能会有很大差异。多么喜欢和哭泣的蛋白质能够适应信号传播的大小和模式以适应环境条件是未知的。基于植物，真菌和动物中LOV和哭泣系统的最新计算和生物物理研究，我们假设Lov/Cry Systems利用动态的构象景观来启用特定于物种和/或环境的环境变量的整合。通过理解这些复杂的景观，我们可以：1）预测相关的生物如何调节昼夜节律对最大化健身。 2）制定操纵生物生理学以纠正有害的策略（疾病引起错误或鼓励有益的适应。在此，我们开发了一个平台，可以修正本科研究人员整合了生物学，生物物理和计算方法。我们专注于两个目的是验证昼夜节律网络中的可塑性。我们特别关注保留变构的系统与哺乳动物中发现的机制相似，从而使我们能够制定新策略来影响人类疾病。目标1：利用最新的计算和结构数据，我们将直接评估变构性开关改变LOV蛋白质构象景观的残留物。特定的重点将放在残留物上允许密切相关的植物和真菌物种在环境特定的方式。我们将演示这些信号网络的可调性，从而开发新方法操纵有机体生理。目标2：利用光活性的最新化学和结构研究脊椎动物哭泣，我们将证明在基于哭泣的系统中存在类似的结构可塑性，允许有机体改变构象反应的大小和方向。使用结构和生化方法我们将开发一种能够操纵哺乳动物昼夜节律网络的光遗传学工具。这合并的方法使我们能够确定用于调整昼夜节网络的自然机制，从而允许设计新的遗传和化学机制来操纵生物体适应性。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Allosteric control of ACE2 peptidase domain dynamics.

DOI：
10.1039/d2ob00606e
发表时间：
2022-05-04
期刊：
Organic & biomolecular chemistry
影响因子：
3.2
作者：
通讯作者：

A tail of CRY selectivity.

CRY 选择性的尾巴。

DOI：
10.1038/s41589-020-0531-z
发表时间：
2020
期刊：
Nature chemical biology
影响因子：
14.8
作者：
Lara,Julia;Zoltowski,BrianD
通讯作者：
Zoltowski,BrianD

Resolving cryptic aspects of cryptochrome signaling.

解决隐花色素信号传导的神秘方面。

DOI：
10.1073/pnas.1511092112
发表时间：
2015
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Zoltowski,BrianD
通讯作者：
Zoltowski,BrianD

LOV-based optogenetic devices: light-driven modules to impart photoregulated control of cellular signaling.