气候变化领域集成服务门户(CCPortal): Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils

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DOI	10.1073/pnas.2015618118
	Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils
	Yang D.S.; Saeedi A.; Davtyan A.; Fathi M.; Sherman M.B.; Safari M.S.; Klindziuk A.; Barton M.C.; Varadarajan N.; Kolomeisky A.B.; Vekilov P.G.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	The protein p53 is a crucial tumor suppressor, often called “the guardian of the genome”; however, mutations transform p53 into a powerful cancer promoter. The oncogenic capacity of mutant p53 has been ascribed to enhanced propensity to fibrillize and recruit other cancer fighting proteins in the fibrils, yet the pathways of fibril nucleation and growth remain obscure. Here, we combine immunofluorescence three-dimensional confocal microscopy of human breast cancer cells with light scattering and transmission electron microscopy of solutions of the purified protein and molecular simulations to illuminate the mechanisms of phase transformations across multiple length scales, from cellular to molecular. We report that the p53 mutant R248Q (R, arginine; Q, glutamine) forms, both in cancer cells and in solutions, a condensate with unique properties, mesoscopic protein-rich clusters. The clusters dramatically diverge from other protein condensates. The cluster sizes are decoupled from the total cluster population volume and independent of the p53 concentration and the solution concentration at equilibrium with the clusters varies. We demonstrate that the clusters carry out a crucial biological function: they host and facilitate the nucleation of amyloid fibrils. We demonstrate that the p53 clusters are driven by structural destabilization of the core domain and not by interactions of its extensive unstructured region, in contradistinction to the dense liquids typical of disordered and partially disordered proteins. Two-step nucleation of mutant p53 amyloids suggests means to control fibrillization and the associated pathologies through modifying the cluster characteristics. Our findings exemplify interactions between distinct protein phases that activate complex physicochemical mechanisms operating in biological systems. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Fibrillization; Nucleation mechanism; Precursors
语种	英语
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/180403
作者单位	William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, United States; Department of Chemistry, Rice University, Houston, TX 77251, United States; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, United States; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States; Center for Theoretical Biological Physics, Rice University, Houston, TX 77251, United States; Department of Chemistry, University of Houston, Houston, TX 77204, United States
推荐引用方式 GB/T 7714	Yang D.S.,Saeedi A.,Davtyan A.,et al. Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils[J],2021,118(10).
APA	Yang D.S..,Saeedi A..,Davtyan A..,Fathi M..,Sherman M.B..,...&Vekilov P.G..(2021).Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Yang D.S.,et al."Mesoscopic protein-rich clusters host the nucleation of mutant p53 amyloid fibrils".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).