Protein misfolding occurs by slow diffusion across multiple barriers in a rough energy landscape

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DOIResolve DOI: https://doi.org/10.1073/pnas.1419197112
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  1. NINT
FormatText
TypeArticle
Journal titleProceedings of the National Academy of Sciences
ISSN0027-8424
1091-6490
Volume112
Issue27
Pages8308–8313
Subjectintrachain diffusion; protein aggregation; prion protein; optical tweezers; single-molecule force spectroscopy
Abstract
The timescale for the microscopic dynamics of proteins during conformational transitions is set by the intrachain diffusion coefficient, D. Despite the central role of protein misfolding and aggregation in many diseases, it has proven challenging to measure D for these processes because of their heterogeneity. We used single-molecule force spectroscopy to overcome these challenges and determine D for misfolding of the prion protein PrP. Observing directly the misfolding of individual dimers into minimal aggregates, we reconstructed the energy landscape governing nonnative structure formation. Remarkably, rather than displaying multiple pathways, as typically expected for aggregation, PrP dimers were funneled into a thermodynamically stable misfolded state along a single pathway containing several intermediates, one of which blocked native folding. Using Kramers’ rate theory, D was found to be 1,000-fold slower for misfolding than for native folding, reflecting local roughening of the misfolding landscape, likely due to increased internal friction. The slow diffusion also led to much longer transit times for barrier crossing, allowing transition paths to be observed directly for the first time to our knowledge. These results open a new window onto the microscopic mechanisms governing protein misfolding.
Publication date
PublisherNational Academy of Sciences
LanguageEnglish
Peer reviewedYes
NPARC number23001590
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Record identifier6fe714e0-bb77-411a-83db-1f3657219712
Record created2017-03-08
Record modified2019-03-12
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