Mechanism of misfolding of the human prion protein revealed by a pathological mutation

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Date
2021-03-23Type
- Journal Article
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Cited 11 times in
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Cited 12 times in
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Abstract
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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000476196Publication status
publishedExternal links
Journal / series
Proceedings of the National Academy of Sciences of the United States of AmericaVolume
Pages / Article No.
Publisher
National Academy of SciencesSubject
Neurodegenerative diseases; Prion protein; Protein misfolding; Amyloid; Transmissible spongiform encephalopathies (TSEs)Organisational unit
02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
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Show all metadata
Citations
Cited 11 times in
Web of Science
Cited 12 times in
Scopus
ETH Bibliography
yes
Altmetrics