ArticleProceedings of the National Academy of Sciences of the United States of America2012
Direct observation of multiple misfolding pathways in a single prion protein molecule.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed.
- Uncovering the protein aggregation process through effect of G41D mutant SOD1 charge variation in ALS disease.Scientific reports · 2025Article
- Review
- 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
- Distinguishing features of fold-switching proteins.Protein science : a publication of the Protein Society · 2023Review
- Enhanced statistical sampling reveals microscopic complexity in the talin mechanosensor folding energy landscape.Nature physics · 2023Article
- Probing the origin of prion protein misfolding via reconstruction of ancestral proteins.Protein science : a publication of the Protein Society · 2022Article
- Evidence of Orientation-Dependent Early States of Prion Protein Misfolded Structures from Single Molecule Force Spectroscopy.Biology · 2022Article
- Tethering Complex Proteins and Protein Complexes for Optical Tweezers Experiments.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Article
- 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
- Tweezepy: A Python package for calibrating forces in single-molecule video-tracking experiments.PloS one · 2021Article
- Optical tweezers in single-molecule biophysics.Nature reviews. Methods primers · 2021Article
- Effects of Ligand Binding on the Energy Landscape of Acyl-CoA-Binding Protein.Biophysical journal · 2020Article
- Entropy-Based Strategies for Rapid Pre-Processing and Classification of Time Series Data from Single-Molecule Force Experiments.Entropy (Basel, Switzerland) · 2020Article
- Single-Molecule Studies of Protein Folding with Optical Tweezers.Annual review of biochemistry · 2020Review
- Slow Transition Path Times Reveal a Complex Folding Barrier in a Designed Protein.Frontiers in chemistry · 2020Article
- Structural insight into conformational change in prion protein by breakage of electrostatic network around H187 due to its protonation.Scientific reports · 2019Article
- Energetic dependencies dictate folding mechanism in a complex protein.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Characterizing the inhibition of α-synuclein oligomerization by a pharmacological chaperone that prevents prion formation by the protein PrP.Protein science : a publication of the Protein Society · 2019Article
- Non-equilibrium dynamics of a nascent polypeptide during translation suppress its misfolding.Nature communications · 2019Article
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8 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Protein misfolding is a ubiquitous phenomenon associated with a wide range of diseases. Single-molecule approaches offer a powerful tool for deciphering the mechanisms of misfolding by measuring the conformational fluctuations of a protein with high sensitivity. We applied single-molecule force spectroscopy to observe directly the misfolding of the prion protein PrP, a protein notable for having an infectious misfolded state that is able to propagate by recruiting natively folded PrP. By measuring folding trajectories of single PrP molecules held under tension in a high-resolution optical trap, we found that the native folding pathway involves only two states, without evidence for partially folded intermediates that have been proposed to mediate misfolding. Instead, frequent but fleeting transitions were observed into off-pathway intermediates. Three different misfolding pathways were detected, all starting from the unfolded state. Remarkably, the misfolding rate was even higher than the rate for native folding. A mutant PrP with higher aggregation propensity showed increased occupancy of some of the misfolded states, suggesting these states may act as intermediates during aggregation. These measurements of individual misfolding trajectories demonstrate the power of single-molecule approaches for characterizing misfolding directly by mapping out nonnative folding pathways.
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