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...

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Autores principales:	Abhishek Upadhyay, Daniela Marzoll, Axel Diernfellner, Michael Brunner, Hanspeter Herzel
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5e843467c919438490c8149ced74124a
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spelling	oai:doaj.org-article:5e843467c919438490c8149ced74124a2021-12-02T13:58:14ZMultiple random phosphorylations in clock proteins provide long delays and switches10.1038/s41598-020-79277-z2045-2322https://doaj.org/article/5e843467c919438490c8149ced74124a2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79277-zhttps://doaj.org/toc/2045-2322Abstract 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 disordered clock proteins (IDPs) using conceptual models of sequential and distributive phosphorylations. Our models help to understand the underlying mechanisms leading to delays and ultrasensitivity. The model shows temporal and steady state switches for the free kinase and the phosphoprotein. We show that random phosphorylations and sequestration mechanisms allow high Hill coefficients required for self-sustained oscillations.Abhishek UpadhyayDaniela MarzollAxel DiernfellnerMichael BrunnerHanspeter HerzelNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abhishek Upadhyay Daniela Marzoll Axel Diernfellner Michael Brunner Hanspeter Herzel Multiple random phosphorylations in clock proteins provide long delays and switches
description	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 disordered clock proteins (IDPs) using conceptual models of sequential and distributive phosphorylations. Our models help to understand the underlying mechanisms leading to delays and ultrasensitivity. The model shows temporal and steady state switches for the free kinase and the phosphoprotein. We show that random phosphorylations and sequestration mechanisms allow high Hill coefficients required for self-sustained oscillations.
format	article
author	Abhishek Upadhyay Daniela Marzoll Axel Diernfellner Michael Brunner Hanspeter Herzel
author_facet	Abhishek Upadhyay Daniela Marzoll Axel Diernfellner Michael Brunner Hanspeter Herzel
author_sort	Abhishek Upadhyay
title	Multiple random phosphorylations in clock proteins provide long delays and switches
title_short	Multiple random phosphorylations in clock proteins provide long delays and switches
title_full	Multiple random phosphorylations in clock proteins provide long delays and switches
title_fullStr	Multiple random phosphorylations in clock proteins provide long delays and switches
title_full_unstemmed	Multiple random phosphorylations in clock proteins provide long delays and switches
title_sort	multiple random phosphorylations in clock proteins provide long delays and switches
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/5e843467c919438490c8149ced74124a
work_keys_str_mv	AT abhishekupadhyay multiplerandomphosphorylationsinclockproteinsprovidelongdelaysandswitches AT danielamarzoll multiplerandomphosphorylationsinclockproteinsprovidelongdelaysandswitches AT axeldiernfellner multiplerandomphosphorylationsinclockproteinsprovidelongdelaysandswitches AT michaelbrunner multiplerandomphosphorylationsinclockproteinsprovidelongdelaysandswitches AT hanspeterherzel multiplerandomphosphorylationsinclockproteinsprovidelongdelaysandswitches
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Multiple random phosphorylations in clock proteins provide long delays and switches

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