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Multiple random phosphorylations in clock proteins provide long delays and switches
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 a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746754/ https://www.ncbi.nlm.nih.gov/pubmed/33335302 http://dx.doi.org/10.1038/s41598-020-79277-z |
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author | Upadhyay, Abhishek Marzoll, Daniela Diernfellner, Axel Brunner, Michael Herzel, Hanspeter |
author_facet | Upadhyay, Abhishek Marzoll, Daniela Diernfellner, Axel Brunner, Michael Herzel, Hanspeter |
author_sort | Upadhyay, Abhishek |
collection | PubMed |
description | 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 | Online Article Text |
id | pubmed-7746754 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-77467542020-12-18 Multiple random phosphorylations in clock proteins provide long delays and switches Upadhyay, Abhishek Marzoll, Daniela Diernfellner, Axel Brunner, Michael Herzel, Hanspeter Sci Rep Article 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. Nature Publishing Group UK 2020-12-17 /pmc/articles/PMC7746754/ /pubmed/33335302 http://dx.doi.org/10.1038/s41598-020-79277-z Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Upadhyay, Abhishek Marzoll, Daniela Diernfellner, Axel Brunner, Michael Herzel, Hanspeter Multiple random phosphorylations in clock proteins provide long delays and switches |
title | 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_short | Multiple random phosphorylations in clock proteins provide long delays and switches |
title_sort | multiple random phosphorylations in clock proteins provide long delays and switches |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746754/ https://www.ncbi.nlm.nih.gov/pubmed/33335302 http://dx.doi.org/10.1038/s41598-020-79277-z |
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