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DOI	10.1126/science.aaw3242
	Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations
	Wilmes S.; Hafer M.; Vuorio J.; Tucker J.A.; Winkelmann H.; Löchte S.; Stanly T.A.; Pulgar Prieto K.D.; Poojari C.; Sharma V.; Richter C.P.; Kurre R.; Hubbard S.R.; Christopher Garcia K.; Moraga I.; Vattulainen I.; Hitchcock I.S.; Piehler J.
发表日期	2020
ISSN	0036-8075
起始页码	643
结束页码	652
卷号	367 期号:6478
英文摘要	Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations. Copyright © 2020 The Authors.
关键词	cytokine receptor homodimer Janus kinase 2 ligand oncoprotein cancer enzyme enzyme activity membrane molecular analysis mutation protein activation analysis Article cell membrane computer model controlled study dimerization fluorescence microscopy gene mutation HeLa cell line molecular dynamics mutant oncogene priority journal protein domain protein interaction quantitative analysis signal transduction
语种	英语
来源机构	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/133738
推荐引用方式 GB/T 7714	Wilmes S.,Hafer M.,Vuorio J.,et al. Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations[J]. Science,2020,367(6478).
APA	Wilmes S..,Hafer M..,Vuorio J..,Tucker J.A..,Winkelmann H..,...&Piehler J..(2020).Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations.,367(6478).
MLA	Wilmes S.,et al."Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations".367.6478(2020).