Multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.

Phosphorylation-triggered degradation is a common strategy for elimination of regulatory proteins in many important cell signaling processes. Interesting examples include cyclin-dependent kinase inhibitors such as p27 in human and Sic1 in yeast, which play crucial roles during the G1/S transition in...

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Autores principales:	S Marjan Varedi K, Alejandra C Ventura, Sofia D Merajver, Xiaoxia Nina Lin
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e31f1825e3944c348a7ccdad23a65a41
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spelling	oai:doaj.org-article:e31f1825e3944c348a7ccdad23a65a412021-11-18T07:01:49ZMultisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.1932-620310.1371/journal.pone.0014029https://doaj.org/article/e31f1825e3944c348a7ccdad23a65a412010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21179196/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Phosphorylation-triggered degradation is a common strategy for elimination of regulatory proteins in many important cell signaling processes. Interesting examples include cyclin-dependent kinase inhibitors such as p27 in human and Sic1 in yeast, which play crucial roles during the G1/S transition in the cell cycle. In this work, we have modeled and analyzed the dynamics of multisite-phosphorylation-triggered protein degradation systematically. Inspired by experimental observations on the Sic1 protein and a previous intriguing theoretical conjecture, we develop a model to examine in detail the degradation dynamics of a protein featuring multiple phosphorylation sites and a threshold site number for elimination in response to a kinase signal. Our model explains the role of multiple phosphorylation sites, compared to a single site, in the regulation of protein degradation. A single-site protein cannot convert a graded input of kinase increase to much sharper output, whereas multisite phosphorylation is capable of generating a highly switch-like temporal profile of the substrate protein with two characteristics: a temporal threshold and rapid decrease beyond the threshold. We introduce a measure termed temporal response coefficient to quantify the extent to which a response in the time domain is switch-like and further investigate how this property is determined by various factors including the kinase input, the total number of sites, the threshold site number for elimination, the order of phosphorylation, the kinetic parameters, and site preference. Some interesting and experimentally verifiable predictions include that the non-degradable fraction of the substrate protein exhibits a more switch-like temporal profile; a sequential system is more switch-like, while a random system has the advantage of increased robustness; all the parameters, including the total number of sites, the threshold site number for elimination and the kinetic parameters synergistically determine the exact extent to which the degradation profile is switch-like. Our results suggest design principles for protein degradation switches which might be a widespread mechanism for precise regulation of cellular processes such as cell cycle progression.S Marjan Varedi KAlejandra C VenturaSofia D MerajverXiaoxia Nina LinPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 12, p e14029 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q S Marjan Varedi K Alejandra C Ventura Sofia D Merajver Xiaoxia Nina Lin Multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.
description	Phosphorylation-triggered degradation is a common strategy for elimination of regulatory proteins in many important cell signaling processes. Interesting examples include cyclin-dependent kinase inhibitors such as p27 in human and Sic1 in yeast, which play crucial roles during the G1/S transition in the cell cycle. In this work, we have modeled and analyzed the dynamics of multisite-phosphorylation-triggered protein degradation systematically. Inspired by experimental observations on the Sic1 protein and a previous intriguing theoretical conjecture, we develop a model to examine in detail the degradation dynamics of a protein featuring multiple phosphorylation sites and a threshold site number for elimination in response to a kinase signal. Our model explains the role of multiple phosphorylation sites, compared to a single site, in the regulation of protein degradation. A single-site protein cannot convert a graded input of kinase increase to much sharper output, whereas multisite phosphorylation is capable of generating a highly switch-like temporal profile of the substrate protein with two characteristics: a temporal threshold and rapid decrease beyond the threshold. We introduce a measure termed temporal response coefficient to quantify the extent to which a response in the time domain is switch-like and further investigate how this property is determined by various factors including the kinase input, the total number of sites, the threshold site number for elimination, the order of phosphorylation, the kinetic parameters, and site preference. Some interesting and experimentally verifiable predictions include that the non-degradable fraction of the substrate protein exhibits a more switch-like temporal profile; a sequential system is more switch-like, while a random system has the advantage of increased robustness; all the parameters, including the total number of sites, the threshold site number for elimination and the kinetic parameters synergistically determine the exact extent to which the degradation profile is switch-like. Our results suggest design principles for protein degradation switches which might be a widespread mechanism for precise regulation of cellular processes such as cell cycle progression.
format	article
author	S Marjan Varedi K Alejandra C Ventura Sofia D Merajver Xiaoxia Nina Lin
author_facet	S Marjan Varedi K Alejandra C Ventura Sofia D Merajver Xiaoxia Nina Lin
author_sort	S Marjan Varedi K
title	Multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.
title_short	Multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.
title_full	Multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.
title_fullStr	Multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.
title_full_unstemmed	Multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.
title_sort	multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/e31f1825e3944c348a7ccdad23a65a41
work_keys_str_mv	AT smarjanvaredik multisitephosphorylationprovidesaneffectiveandflexiblemechanismforswitchlikeproteindegradation AT alejandracventura multisitephosphorylationprovidesaneffectiveandflexiblemechanismforswitchlikeproteindegradation AT sofiadmerajver multisitephosphorylationprovidesaneffectiveandflexiblemechanismforswitchlikeproteindegradation AT xiaoxianinalin multisitephosphorylationprovidesaneffectiveandflexiblemechanismforswitchlikeproteindegradation
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Multisite phosphorylation provides an effective and flexible mechanism for switch-like protein degradation.

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