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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Sosova, Iveta Yu, Hao Woodside, Michael T. Dee, Derek R. Brigley, Angela M. Liu, Xia |
| Description | Author Affiliation: Yu H ( Department of Physics, University of Alberta, Edmonton, AB, T6G 2E1, Canada); Dee DR ( Department of Physics, University of Alberta, Edmonton, AB, T6G 2E1, Canada); Liu X ( Department of Physics, University of Alberta, Edmonton, AB, T6G 2E1, Canada); Brigley AM ( National Institute for Nanotechnology, National Research Council, Edmonton, AB, T6G 2M9, Canada.); Sosova I ( National Institute for Nanotechnology, National Research Council, Edmonton, AB, T6G 2M9, Canada.); Woodside MT ( Department of Physics, University of Alberta, Edmonton, AB, T6G 2E1, Canada); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 27 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Prions Chemistry Protein Folding Protein Multimerization Thermodynamics Algorithms Animals Cricetinae Diffusion Mesocricetus Models, Chemical Models, Molecular Peptide Fragments Spectrum Analysis Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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