气候变化领域集成服务门户(CCPortal): Molecular switch architecture determines response properties of signaling pathways

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DOI	10.1073/pnas.2013401118
	Molecular switch architecture determines response properties of signaling pathways
	Ghusinga K.R.; Jones R.D.; Jones A.M.; Elston T.C.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Many intracellular signaling pathways are composed of molecular switches, proteins that transition between two states-on and off. Typically, signaling is initiated when an external stimulus activates its cognate receptor that, in turn, causes downstream switches to transition from off to on using one of the following mechanisms: activation, in which the transition rate from the off state to the on state increases derepression, in which the transition rate from the on state to the off state decreases; and concerted, in which activation and derepression operate simultaneously. We use mathematical modeling to compare these signaling mechanisms in terms of their dose-response curves, response times, and abilities to process upstream fluctuations. Our analysis elucidates several operating principles for molecular switches. First, activation increases the sensitivity of the pathway, whereas derepression decreases sensitivity. Second, activation generates response times that decrease with signal strength, whereas derepression causes response times to increase with signal strength. These opposing features allow the concerted mechanism to not only show dose-response alignment, but also to decouple the response time from stimulus strength. However, these potentially beneficial properties come at the expense of increased susceptibility to upstream fluctuations. We demonstrate that these operating principles also hold when the models are extended to include additional features, such as receptor removal, kinetic proofreading, and cascades of switches. In total, we show how the architecture of molecular switches govern their response properties. We also discuss the biological implications of our findings. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Activation; Derepression; Dose-response; Noise; Signaling pathways
语种	英语
scopus关键词	article; degradation kinetics; dose response; noise; reaction time; signal transduction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180253
作者单位	Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States; Center for Complex Systems and Enterprises, Stevens Institute of Technology, Hoboken, NJ 07030, United States
推荐引用方式 GB/T 7714	Ghusinga K.R.,Jones R.D.,Jones A.M.,et al. Molecular switch architecture determines response properties of signaling pathways[J],2021,118(11).
APA	Ghusinga K.R.,Jones R.D.,Jones A.M.,&Elston T.C..(2021).Molecular switch architecture determines response properties of signaling pathways.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Ghusinga K.R.,et al."Molecular switch architecture determines response properties of signaling pathways".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).