气候变化领域集成服务门户(CCPortal): Physical mechanisms of amyloid nucleation on fluid membranes

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DOI	10.1073/PNAS.2007694117
	Physical mechanisms of amyloid nucleation on fluid membranes
	Krausser J.; Knowles T.P.J.; Šarić A.-E.
发表日期	2021
ISSN	00278424
起始页码	33090
结束页码	33098
卷号	117 期号:52
英文摘要	Biological membranes can dramatically accelerate the aggregation of normally soluble protein molecules into amyloid fibrils and alter the fibril morphologies, yet the molecular mechanisms through which this accelerated nucleation takes place are not yet understood. Here, we develop a coarse-grained model to systematically explore the effect that the structural properties of the lipid membrane and the nature of protein–membrane interactions have on the nucleation rates of amyloid fibrils. We identify two physically distinct nucleation pathways—protein-rich and lipid-rich—and quantify how the membrane fluidity and protein–membrane affinity control the relative importance of those molecular pathways. We find that the membrane’s susceptibility to reshaping and being incorporated into the fibrillar aggregates is a key determinant of its ability to promote protein aggregation. We then characterize the rates and the free-energy profile associated with this heterogeneous nucleation process, in which the surface itself participates in the aggregate structure. Finally, we compare quantitatively our data to experiments on membrane-catalyzed amyloid aggregation of α-synuclein, a protein implicated in Parkinson’s disease that predominately nucleates on membranes. More generally, our results provide a framework for understanding macromolecular aggregation on lipid membranes in a broad biological and biotechnological context. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Amyloid; Cell membrane; Coarse-grained simulations; Membrane fluidity; Protein aggregation
语种	英语
scopus关键词	amyloid; membrane lipid; cell membrane; chemistry; computer simulation; lipid bilayer; membrane fluidity; Amyloid; Cell Membrane; Computer Simulation; Lipid Bilayers; Membrane Fluidity; Membrane Lipids
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/179649
作者单位	Department of Physics and Astronomy, Institute for the Physics of Living Systems, University College London, London, WC1E 6BT, United Kingdom; Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, WC1E 6BT, United Kingdom; Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom; Cavendish Laboratory, University of Cambridge, Cambridge, CB3 0HE, United Kingdom
推荐引用方式 GB/T 7714	Krausser J.,Knowles T.P.J.,Šarić A.-E.. Physical mechanisms of amyloid nucleation on fluid membranes[J],2021,117(52).
APA	Krausser J.,Knowles T.P.J.,&Šarić A.-E..(2021).Physical mechanisms of amyloid nucleation on fluid membranes.Proceedings of the National Academy of Sciences of the United States of America,117(52).
MLA	Krausser J.,et al."Physical mechanisms of amyloid nucleation on fluid membranes".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021).