ArticleProceedings of the National Academy of Sciences of the United States of America2004
Demonstration of a low-energy on-pathway intermediate in a fast-folding protein by kinetics, protein engineering, and simulation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- A Fluorescence-Based Temperature-Jump Apparatus for Illustrating Protein Dynamics on the Millisecond Time Scale.Analytical chemistry · 2025Article
- Mapping the FF domain folding pathway via structures of transiently populated folding intermediates.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural-Energetic Basis for Coupling between Equilibrium Fluctuations and Phosphorylation in a Protein Native Ensemble.ACS central science · 2022Article
- The A39G FF domain folds on a volcano-shaped free energy surface via separate pathways.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Stability of an aggregation-prone partially folded state of human profilin-1 correlates with aggregation propensity.The Journal of biological chemistry · 2018Article
- Identification and Structural Characterization of an Intermediate in the Folding of the Measles Virus X Domain.The Journal of biological chemistry · 2016Article
- Shear-stress-mediated refolding of proteins from aggregates and inclusion bodies.Chembiochem : a European journal of chemical biology · 2015Article
- Article
- NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Early steps in thermal unfolding of superoxide dismutase 1 are similar to the conformational changes associated with the ALS-associated A4V mutation.Protein engineering, design & selection : PEDS · 2013Article
- Probing slowly exchanging protein systems via ¹³Cα-CEST: monitoring folding of the Im7 protein.Journal of biomolecular NMR · 2013Article
- The N-terminal helix controls the transition between the soluble and amyloid states of an FF domain.PloS one · 2013Article
- Reassessing the folding of the KIX domain: evidence for a two-state mechanism.Protein science : a publication of the Protein Society · 2012Article
- Transiently populated intermediate functions as a branching point of the FF domain folding pathway.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- The effect of C-terminal helix on the stability of FF domain studied by molecular dynamics simulation.International journal of molecular sciences · 2012Article
- Nonnative interactions in the FF domain folding pathway from an atomic resolution structure of a sparsely populated intermediate: an NMR relaxation dispersion study.Journal of the American Chemical Society · 2011Article
- Malleability of folding intermediates in the homeodomain superfamily.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Structural characterization of a misfolded intermediate populated during the folding process of a PDZ domain.Nature structural & molecular biology · 2010Article
- The plastic energy landscape of protein folding: a triangular folding mechanism with an equilibrium intermediate for a small protein domain.The Journal of biological chemistry · 2010Article
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7 authors.
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Abstract
It is controversial whether fast-folding proteins can form productive on-pathway intermediates that are more stable than the denatured state because noncovalent intermediates are usually evanescent. Here, we apply the classical criteria for the existence of intermediates: namely, the intermediates form and react rapidly enough to be on pathway and they can be isolated and characterized. The folding of the 71-residue, mainly alpha-helical FF domain from human HYPA/FBP11 fulfills these classical criteria, as was found for Im7. The FF domain folds in two phases, one on the micros and the other on the ms time scale. An engineered mutant folds only to a partly folded state, with some 20-40% of the native helical content. The kinetic properties of the mutant are identical to those found for the fast phase of the wild-type protein, and it is likely that the mutant folds just to the intermediate state. A full kinetic analysis of the folding of wild-type protein, using the amplitudes of its native and denatured states and the observed values for the mutant, rules out an off-pathway scheme but fits an on-pathway scheme, with a low energy intermediate that is modeled by the mutant. The experimental proof benchmarks a molecular dynamics method that identifies an obligatory intermediate observed in multiple simulations. The conformational space defining this intermediate is visited several times in the simulations, leading to high populations consistent with the presence of a low energy intermediate.
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