Bayesian modeling reveals metabolite‐dependent ultrasensitivity in the cyanobacterial circadian clock

Li, Hong; Lavrentovich, Danylo; Chavan, Archana G.; Leypunskiy, Eugene; Li, Eileen; Matthews, Charles H.; LiWang, Andy; Rust, Michael J.; Dinner, Aaron R.

doi:10.15252/msb.20199355

Cited by 12 publications

(15 citation statements)

References 121 publications

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“…That being said, the mechanisms we discuss are far from a complete picture of circadian timekeeping. In fact, factors like co-operative binding or ultrasensitivity also play key roles [35,36].…”

Section: Discussionmentioning

confidence: 99%

Evolution of the repression mechanisms in circadian clocks

Tyler

Dunlap

et al. 2022

Genome Biol

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Background Circadian (daily) timekeeping is essential to the survival of many organisms. An integral part of all circadian timekeeping systems is negative feedback between an activator and repressor. However, the role of this feedback varies widely between lower and higher organisms. Results Here, we study repression mechanisms in the cyanobacterial and eukaryotic clocks through mathematical modeling and systems analysis. We find a common mathematical model that describes the mechanism by which organisms generate rhythms; however, transcription’s role in this has diverged. In cyanobacteria, protein sequestration and phosphorylation generate and regulate rhythms while transcription regulation keeps proteins in proper stoichiometric balance. Based on recent experimental work, we propose a repressor phospholock mechanism that models the negative feedback through transcription in clocks of higher organisms. Interestingly, this model, when coupled with activator phosphorylation, allows for oscillations over a wide range of protein stoichiometries, thereby reconciling the negative feedback mechanism in Neurospora with that in mammals and cyanobacteria. Conclusions Taken together, these results paint a picture of how circadian timekeeping may have evolved.

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Section: Discussionmentioning

confidence: 99%

Evolution of the repression mechanisms in circadian clocks

Tyler

Dunlap

et al. 2022

Genome Biol

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“…Intriguingly, quantitative modeling has suggested that nutrient-dependent FRH sequestration away from the negative arm complex is a plausible mechanism for Nutritional Compensation (Upadhyay et al, 2019). Mechanistic work in prokaryotes has indicated that Nutritional Compensation can be derived from the same core clock enzyme, KaiC, through its protein domains with equal and opposite balancing reaction rates (Phong et al, 2013; Hong et al, 2020). In fungi and perhaps other eukaryotic clocks, Nutritional Compensation appears to be maintained through regulation of multiple different core clock factors.…”

Section: Discussionmentioning

confidence: 99%

A role for gene expression and mRNA stability in nutritional compensation of the circadian clock

Kelliher

Stevenson

Loros

et al. 2022

Preprint

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Compensation is a defining principle of a true circadian clock, where its approximately 24-hour period length is relatively unchanged across environmental conditions. Known compensation effectors directly regulate core clock factors to buffer the oscillator's period length from variables in the environment. Temperature Compensation mechanisms have been experimentally addressed across circadian model systems, but much less is known about the related process of Nutritional Compensation, where circadian period length is maintained across physiologically relevant nutrient levels. Using the filamentous fungus Neurospora crassa, we performed a genetic screen under glucose and amino acid starvation conditions to identify new regulators of Nutritional Compensation. Our screen uncovered 16 novel mutants, and together with 4 mutants characterized in prior work, a model emerges where Nutritional Compensation of the fungal clock is achieved at the levels of transcription, chromatin regulation, and mRNA stability. However, eukaryotic circadian Nutritional Compensation is completely unstudied outside of Neurospora. To test for conservation in cultured mammalian cells, we selected the top two hits from our fungal genetic screen, performed siRNA knockdown experiments of the mammalian homologs, and characterized the cell lines with respect to compensation. We find that the wild-type mammalian clock is also compensated across a large range of external glucose concentrations, as observed in Neurospora, and that knocking down CPSF6 or SETD2 in human cells also results in nutrient-dependent period length changes. We conclude that, like Temperature Compensation, Nutritional Compensation is a conserved circadian process in fungal and mammalian clocks and that it may share common molecular determinants.

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“…However, a significant amount of free KaiA protein was still present in the reaction mixture when KaiC was ready to start the dephosphorylation phase [ 26 , 28 ]. A decrease in free KaiA due to sequestration by KaiB would not necessarily have reversed the kinase reaction; rather, it would have just slowed it down [ 24 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Shift in Conformational Equilibrium Underlies the Oscillatory Phosphoryl Transfer Reaction in the Circadian Clock

Kim

Thati

Peshori

et al. 2021

Life

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Oscillatory phosphorylation/dephosphorylation can be commonly found in a biological system as a means of signal transduction though its pivotal presence in the workings of circadian clocks has drawn significant interest: for example in a significant portion of the physiology of Synechococcus elongatus PCC 7942. The biological oscillatory reaction in the cyanobacterial circadian clock can be visualized through its reconstitution in a test tube by mixing three proteins—KaiA, KaiB and KaiC—with adenosine triphosphate and magnesium ions. Surprisingly, the oscillatory phosphorylation/dephosphorylation of the hexameric KaiC takes place spontaneously and almost indefinitely in a test tube as long as ATP is present. This autonomous post-translational modification is tightly regulated by the conformational change of the C-terminal peptide of KaiC called the “A-loop” between the exposed and the buried states, a process induced by the time-course binding events of KaiA and KaiB to KaiC. There are three putative hydrogen-bond forming residues of the A-loop that are important for stabilizing its buried conformation. Substituting the residues with alanine enabled us to observe KaiB’s role in dephosphorylating hyperphosphorylated KaiC, independent of KaiA’s effect. We found a novel role of KaiB that its binding to KaiC induces the A-loop toward its buried conformation, which in turn activates the autodephosphorylation of KaiC. In addition to its traditional role of sequestering KaiA, KaiB’s binding contributes to the robustness of cyclic KaiC phosphorylation by inhibiting it during the dephosphorylation phase, effectively shifting the equilibrium toward the correct phase of the clock.

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Bayesian modeling reveals metabolite‐dependent ultrasensitivity in the cyanobacterial circadian clock

Cited by 12 publications

References 121 publications

Evolution of the repression mechanisms in circadian clocks

Evolution of the repression mechanisms in circadian clocks

A role for gene expression and mRNA stability in nutritional compensation of the circadian clock

Shift in Conformational Equilibrium Underlies the Oscillatory Phosphoryl Transfer Reaction in the Circadian Clock

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