气候变化领域集成服务门户(CCPortal): Mechanism of misfolding of the human prion protein revealed by a pathological mutation

CCPortal

DOI	10.1073/pnas.2019631118
	Mechanism of misfolding of the human prion protein revealed by a pathological mutation
	Sanz-Hernández M.; Barritt J.D.; Sobek J.; Hornemann S.; Aguzzi A.; de Simone A.
发表日期	2021
ISSN	00278424
卷号	118 期号:12
英文摘要	The misfolding and aggregation of the human prion protein (PrP) is associated with transmissible spongiform encephalopathies (TSEs). Intermediate conformations forming during the conversion of the cellular form of PrP into its pathological scrapie conformation are key drivers of the misfolding process. Here, we analyzed the properties of the C-terminal domain of the human PrP (huPrP) and its T183A variant, which is associated with familial forms of TSEs. We show that the mutation significantly enhances the aggregation propensity of huPrP, such as to uniquely induce amyloid formation under physiological conditions by the sole C-terminal domain of the protein. Using NMR spectroscopy, biophysics, and metadynamics simulations, we identified the structural characteristics of the misfolded intermediate promoting the aggregation of T183A huPrP and the nature of the interactions that prevent this species to be populated in the wild-type protein. In support of these conclusions, POM antibodies targeting the regions that promote PrP misfolding were shown to potently suppress the aggregation of this amyloidogenic mutant. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Neurodegenerative diseases \| prion protein \| protein misfolding \| amyloid \| transmissible spongiform encephalopathies (TSEs)
语种	英语
scopus关键词	amyloid protein; prion protein; Article; biophysics; carboxy terminal sequence; controlled study; Escherichia coli; gene; gene mutation; genetic variability; human; molecular dynamics; mutational analysis; nonhuman; nuclear magnetic resonance; physiological process; prion disease; priority journal; protein aggregation; protein domain; protein function; protein interaction; protein misfolding; protein structure; protein targeting; structure analysis; T183A gene; wild type
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/180192
作者单位	Department of Life Sciences, Imperial College London, South-Kensington, SW7 2AZ, United Kingdom; Functional Genomics Center Zurich, ETH Zurich, University of Zurich, Zurich, 8057, Switzerland; Institute of Neuropathology, University of Zurich, Zurich, 8091, Switzerland; Department of Pharmacy, University of Naples “Federico II,, Naples, 80131, Italy
推荐引用方式 GB/T 7714	Sanz-Hernández M.,Barritt J.D.,Sobek J.,et al. Mechanism of misfolding of the human prion protein revealed by a pathological mutation[J],2021,118(12).
APA	Sanz-Hernández M.,Barritt J.D.,Sobek J.,Hornemann S.,Aguzzi A.,&de Simone A..(2021).Mechanism of misfolding of the human prion protein revealed by a pathological mutation.Proceedings of the National Academy of Sciences of the United States of America,118(12).
MLA	Sanz-Hernández M.,et al."Mechanism of misfolding of the human prion protein revealed by a pathological mutation".Proceedings of the National Academy of Sciences of the United States of America 118.12(2021).