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  • 标题:Mechanism of misfolding of the human prion protein revealed by a pathological mutation
  • 本地全文:下载
  • 作者:Máximo Sanz-Hernández ; Joseph D. Barritt ; Jens Sobek
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2021
  • 卷号:118
  • 期号:12
  • 页码:1
  • DOI:10.1073/pnas.2019631118
  • 出版社:The National Academy of Sciences of the United States of America
  • 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.
  • 关键词:neurodegenerative diseases ; prion protein ; protein misfolding ; amyloid ; transmissible spongiform encephalopathies (TSEs)
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