ArticleProceedings of the National Academy of Sciences of the United States of America2015
Protein misfolding occurs by slow diffusion across multiple barriers in a rough energy landscape.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
- Static and dynamic rough energy landscapes can lead to identical diffusivity.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Lysine-Targeting Inhibitors of Amyloidogenic Protein Aggregation: A Promise for Neurodegenerative Proteinopathies.JACS Au · 2025Review
- Different folding mechanisms in prion proteins from mammals with different disease susceptibility observed at the single-molecule level.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Beyond Misfolding: A New Paradigm for the Relationship Between Protein Folding and Aggregation.International journal of molecular sciences · 2024Review
- Direct observation of prion-like propagation of protein misfolding templated by pathogenic mutants.Nature chemical biology · 2024Article
- A Perspective on Interdicting in Protein Misfolding for Therapeutic Drug Design: Modulating the Formation of Nonlocal Contacts in α-Synuclein as a Strategy against Parkinson's Disease.The journal of physical chemistry. B · 2024Review
- Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications.Pharmacological reviews · 2023Review
- Evidence of Orientation-Dependent Early States of Prion Protein Misfolded Structures from Single Molecule Force Spectroscopy.Biology · 2022Article
- Observing the base-by-base search for native structure along transition paths during the folding of single nucleic acid hairpins.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- The Proteome Folding Problem and Cellular Proteostasis.Journal of molecular biology · 2021Review
- Internalization of α-synuclein oligomers into SH-SY5Y cells.Biophysical journal · 2021Article
- Unfolded and intermediate states of PrP play a key role in the mechanism of action of an antiprion chaperone.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Optical tweezers in single-molecule biophysics.Nature reviews. Methods primers · 2021Article
- Visualizing and trapping transient oligomers in amyloid assembly pathways.Biophysical chemistry · 2021Review
- A potential role for a novel ZC3H5 complex in regulating mRNA translation inThe Journal of biological chemistry · 2020Article
- Single-Molecule Studies of Protein Folding with Optical Tweezers.Annual review of biochemistry · 2020Review
- Cross-Species and Cross-Polymorph Seeding of Lysozyme Amyloid Reveals a Dominant Polymorph.Frontiers in molecular biosciences · 2020Article
- Spontaneous self-assembly of amyloid β (1-40) into dimers.Nanoscale advances · 2019Article
- Infinite Assembly of Folded Proteins in Evolution, Disease, and Engineering.Angewandte Chemie (International ed. in English) · 2019Review
- Size and topology modulate the effects of frustration in protein folding.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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