2020
DOI: 10.1038/s41598-020-79277-z
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Multiple random phosphorylations in clock proteins provide long delays and switches

Abstract: Theory predicts that self-sustained oscillations require robust delays and nonlinearities (ultrasensitivity). Delayed negative feedback loops with switch-like inhibition of transcription constitute the core of eukaryotic circadian clocks. The kinetics of core clock proteins such as PER2 in mammals and FRQ in Neurospora crassa is governed by multiple phosphorylations. We investigate how multiple, slow and random phosphorylations control delay and molecular switches. We model phosphorylations of intrinsically di… Show more

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Cited by 10 publications
(10 citation statements)
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“…While stable number and sites of modifications may allow for programmed phase-locking events with individual proteins more locally (such as phosphorylating a protein that is essential to couple, say, only one round of cytokinesis to every mitosis), bursts of futile modifications on disordered peptide chunks may promote more rapid synchronization at a global level, particularly in response to homeostatic events such as growth signals and metabolic cues. Computational and systems-level studies that have examined the bulk phosphorylation events in circadian ( Upadhyay et al, 2020 ) and cell cycle regulation ( Swaffer et al, 2016 ; Tyanova et al, 2013 ) draw similar conclusions to the latter part of our speculation. With a few exceptions in vivo ( Deshaies and Ferrell, 2001 ; Nash et al, 2001 ), the former idea is pending to be vigorously tested in vitro for residue specificities.…”
Section: The Logic and Potential Evolutionary Origins Of Autonomous Clockssupporting
confidence: 78%
“…While stable number and sites of modifications may allow for programmed phase-locking events with individual proteins more locally (such as phosphorylating a protein that is essential to couple, say, only one round of cytokinesis to every mitosis), bursts of futile modifications on disordered peptide chunks may promote more rapid synchronization at a global level, particularly in response to homeostatic events such as growth signals and metabolic cues. Computational and systems-level studies that have examined the bulk phosphorylation events in circadian ( Upadhyay et al, 2020 ) and cell cycle regulation ( Swaffer et al, 2016 ; Tyanova et al, 2013 ) draw similar conclusions to the latter part of our speculation. With a few exceptions in vivo ( Deshaies and Ferrell, 2001 ; Nash et al, 2001 ), the former idea is pending to be vigorously tested in vitro for residue specificities.…”
Section: The Logic and Potential Evolutionary Origins Of Autonomous Clockssupporting
confidence: 78%
“…The cooperative nature of allosteric regulation is a source of nonlinearity that gives rise to oscillatory phenomena in diverse cellular functions ( 1, 2 ). Circadian clock systems are a typical example, wherein clock proteins are post-translationally phosphorylated at multiple sites in programmed ( 3-5 ) or pseudo-random manners ( 6, 7 ) as a means to allosterically regulate the stability of hetero-multimeric complexes of clock proteins ( 8, 9 ), delays for feedback loops ( 6 ), and period length ( 10 ). Accordingly, a great deal of effort has been devoted to characterizing the phosphorylation-dependent allosteric structural changes in the clock proteins along the circadian reaction coordinate ( 8, 9, 11-15 ).…”
Section: Main Textmentioning
confidence: 99%
“…FRH localizes FRQ to the cytosol after WCC repression, which could tune WCC activity (Cha et al, 2011). FRH may also regulate the phosphorylation rate of FRQ, a parameter that is important for self-sustained oscillations, though the ATPase function of FRH is not necessary for clock function (Hurley et al, 2013; Lauinger et al, 2014; Upadhyay et al, 2020). In higher eukaryotes, another negative arm protein, CRYPTOCHROME (CRY), contributes to clock robustness rather than feedback (Putker et al, 2021).…”
Section: Discussionmentioning
confidence: 99%