Organisms exploit predictable environmental light/dark cycles by systematically varying their metabolism, physiology, and behavior in synchrony with day and night. These circadian rhythms, which are produced by molecular clocks, can have profound consequences to health and disease if disrupted. However, the mechanisms of these circadian clocks are only partially understood in any organism. Because a rigorous understanding of these mechanisms will be indispensable for tackling circadian elated diseases, the long-term goal of the LiWang research group is to elucidate the mechanisms of clocks and clock control over cellular processes in model systems. Reports in the literature and data from this laboratory strongly suggest that clock proteins rearrange their global conformations, and thus their functional properties, as part of the timekeeping mechanism. For example, pace-setter proteins, PER in animals and FRQ in fungi, undergo conformational changes between globally compact and open states as they keep time. Similarly, we recently discovered that the cyanobacteria clock protein, KaiB, also executes global conformational rearrangements, KaiB ? KaiB*, called """"""""fold switching"""""""". Surprisingly, we also found that KaiB fold switching not only plays an essential role in the generation of circadian rhythms, but regulates the transmission of those rhythms downstream. Thus, the objective here is to elucidate the roles of large-scale conformational changes by proteins in clock mechanisms. Attaining this goal is predicted to have an enormous influence on the field of both prokaryotic and eukaryotic chronobiology. The central hypothesis of this proposal is that KaiB ? KaiB* fold switching is the linchpin that joins oscillator function to clock output. To test the central hypothesis we will pursue three specific aims: 1) Establish the role of KaiB ? KaiB* fold switching in oscillator functions;2) Determine how KaiB ? KaiB* fold switching regulates the SasA output pathway;and 3) Determine how KaiB ? KaiB* fold switching regulates the CikA output pathway. The central hypothesis is strongly supported by preliminary data obtained by using an integrative approach: structures ? mutants'? in vitro experiments ? computational modeling ? in vivo experiments. A strong team of collaborators with expertise in each area enhances the feasibility of the work proposed. This proposal is innovative, because a lack of reports in the literature reveals that the central concept of this proposal has been overlooked: Large changes in protein structure underpin the mechanisms of circadian clocks. The proposal is significant, because the findings here are expected to open new and actionable insights into eukaryotic clocks, and to other processes in which protein fold switching may not have been previously recognized. Ultimately, such knowledge has the potential to create strategies with which to tackle circadian-related diseases.

Public Health Relevance

The proposed research is relevant to public health because by providing a rigorous understanding into the mechanisms of circadian clocks, it removes a major barrier to establishing how clocks orchestrate gene expression, metabolism, and cell cycle progression - a prerequisite for gaining indispensable insights into the pathogenesis of circadian-related diseases such as obesity, diabetes, cancer, asthma, cardiovascular disease, and neurodegeneration. Thus, the proposed research is relevant to the part of NIH's mission that pertains to the pursuit of fundamental knowledge that will help extend healthy life and reduce the burdens of illness.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1)
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Sesma, Michael A
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University of California Merced
Earth Sciences/Resources
United States
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Welkie, David G; Rubin, Benjamin E; Chang, Yong-Gang et al. (2018) Genome-wide fitness assessment during diurnal growth reveals an expanded role of the cyanobacterial circadian clock protein KaiA. Proc Natl Acad Sci U S A 115:E7174-E7183
Swan, Jeffrey A; Golden, Susan S; LiWang, Andy et al. (2018) Structure, function, and mechanism of the core circadian clock in cyanobacteria. J Biol Chem 293:5026-5034
Tseng, Roger; Goularte, Nicolette F; Chavan, Archana et al. (2017) Structural basis of the day-night transition in a bacterial circadian clock. Science 355:1174-1180
Chang, Yong-Gang; Cohen, Susan E; Phong, Connie et al. (2015) Circadian rhythms. A protein fold switch joins the circadian oscillator to clock output in cyanobacteria. Science 349:324-8
Tseng, Roger; Chang, Yong-Gang; Bravo, Ian et al. (2014) Cooperative KaiA-KaiB-KaiC interactions affect KaiB/SasA competition in the circadian clock of cyanobacteria. J Mol Biol 426:389-402
Chang, Yong-Gang; Tseng, Roger; Kuo, Nai-Wei et al. (2013) Nuclear magnetic resonance spectroscopy of the circadian clock of cyanobacteria. Integr Comp Biol 53:93-102