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A thermodynamically consistent model of the post-translational Kai circadian clock
The principal pacemaker of the circadian clock of the cyanobacterium S. elongatus is a protein phosphorylation cycle consisting of three proteins, KaiA, KaiB and KaiC. KaiC forms a homohexamer, with each monomer consisting of two domains, CI and CII. Both domains can bind and hydrolyze ATP, but only...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371392/ https://www.ncbi.nlm.nih.gov/pubmed/28296888 http://dx.doi.org/10.1371/journal.pcbi.1005415 |
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author | Paijmans, Joris Lubensky, David K. ten Wolde, Pieter Rein |
author_facet | Paijmans, Joris Lubensky, David K. ten Wolde, Pieter Rein |
author_sort | Paijmans, Joris |
collection | PubMed |
description | The principal pacemaker of the circadian clock of the cyanobacterium S. elongatus is a protein phosphorylation cycle consisting of three proteins, KaiA, KaiB and KaiC. KaiC forms a homohexamer, with each monomer consisting of two domains, CI and CII. Both domains can bind and hydrolyze ATP, but only the CII domain can be phosphorylated, at two residues, in a well-defined sequence. While this system has been studied extensively, how the clock is driven thermodynamically has remained elusive. Inspired by recent experimental observations and building on ideas from previous mathematical models, we present a new, thermodynamically consistent, statistical-mechanical model of the clock. At its heart are two main ideas: i) ATP hydrolysis in the CI domain provides the thermodynamic driving force for the clock, switching KaiC between an active conformational state in which its phosphorylation level tends to rise and an inactive one in which it tends to fall; ii) phosphorylation of the CII domain provides the timer for the hydrolysis in the CI domain. The model also naturally explains how KaiA, by acting as a nucleotide exchange factor, can stimulate phosphorylation of KaiC, and how the differential affinity of KaiA for the different KaiC phosphoforms generates the characteristic temporal order of KaiC phosphorylation. As the phosphorylation level in the CII domain rises, the release of ADP from CI slows down, making the inactive conformational state of KaiC more stable. In the inactive state, KaiC binds KaiB, which not only stabilizes this state further, but also leads to the sequestration of KaiA, and hence to KaiC dephosphorylation. Using a dedicated kinetic Monte Carlo algorithm, which makes it possible to efficiently simulate this system consisting of more than a billion reactions, we show that the model can describe a wealth of experimental data. |
format | Online Article Text |
id | pubmed-5371392 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-53713922017-04-06 A thermodynamically consistent model of the post-translational Kai circadian clock Paijmans, Joris Lubensky, David K. ten Wolde, Pieter Rein PLoS Comput Biol Research Article The principal pacemaker of the circadian clock of the cyanobacterium S. elongatus is a protein phosphorylation cycle consisting of three proteins, KaiA, KaiB and KaiC. KaiC forms a homohexamer, with each monomer consisting of two domains, CI and CII. Both domains can bind and hydrolyze ATP, but only the CII domain can be phosphorylated, at two residues, in a well-defined sequence. While this system has been studied extensively, how the clock is driven thermodynamically has remained elusive. Inspired by recent experimental observations and building on ideas from previous mathematical models, we present a new, thermodynamically consistent, statistical-mechanical model of the clock. At its heart are two main ideas: i) ATP hydrolysis in the CI domain provides the thermodynamic driving force for the clock, switching KaiC between an active conformational state in which its phosphorylation level tends to rise and an inactive one in which it tends to fall; ii) phosphorylation of the CII domain provides the timer for the hydrolysis in the CI domain. The model also naturally explains how KaiA, by acting as a nucleotide exchange factor, can stimulate phosphorylation of KaiC, and how the differential affinity of KaiA for the different KaiC phosphoforms generates the characteristic temporal order of KaiC phosphorylation. As the phosphorylation level in the CII domain rises, the release of ADP from CI slows down, making the inactive conformational state of KaiC more stable. In the inactive state, KaiC binds KaiB, which not only stabilizes this state further, but also leads to the sequestration of KaiA, and hence to KaiC dephosphorylation. Using a dedicated kinetic Monte Carlo algorithm, which makes it possible to efficiently simulate this system consisting of more than a billion reactions, we show that the model can describe a wealth of experimental data. Public Library of Science 2017-03-15 /pmc/articles/PMC5371392/ /pubmed/28296888 http://dx.doi.org/10.1371/journal.pcbi.1005415 Text en © 2017 Paijmans et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Paijmans, Joris Lubensky, David K. ten Wolde, Pieter Rein A thermodynamically consistent model of the post-translational Kai circadian clock |
title | A thermodynamically consistent model of the post-translational Kai circadian clock |
title_full | A thermodynamically consistent model of the post-translational Kai circadian clock |
title_fullStr | A thermodynamically consistent model of the post-translational Kai circadian clock |
title_full_unstemmed | A thermodynamically consistent model of the post-translational Kai circadian clock |
title_short | A thermodynamically consistent model of the post-translational Kai circadian clock |
title_sort | thermodynamically consistent model of the post-translational kai circadian clock |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371392/ https://www.ncbi.nlm.nih.gov/pubmed/28296888 http://dx.doi.org/10.1371/journal.pcbi.1005415 |
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