ArticleScience advances2025
Protein misfolding involving entanglements providesa structural explanation for the origin of stretched-exponential refolding kinetics.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Protein entanglement misfolding influences whether proteins undergo proteasomal degradation or persist in near-native misfolded states.Nature communications · 2026Article
- Natively entangled proteins are linked to human disease and pathogenic mutations likely due to a greater misfolding propensity.bioRxiv : the preprint server for biology · 2026Article
- Detecting misfolded non-covalent lasso entanglements in protein structures, simulation trajectories, and mass spectrometry data.bioRxiv : the preprint server for biology · 2026Article
- Native entanglement misfolding contributes to age-associated structural changebioRxiv : the preprint server for biology · 2026Article
- Phosphoglycerate Kinase Can Adopt Topologically Misfolded Forms That Are More Stable Than Its Native State.Journal of the American Chemical Society · 2026Article
- Chaperone dependency during biogenesis does not correlate with chaperone dependency during refolding.Molecular systems biology · 2026Article
- A widespread protein misfolding mechanism is differentially rescued in vitro by chaperones based on gene essentiality.Nature communications · 2025Article
- Observing Picomolar Protein Unfolding Using Resonance Light Scattering.Biomolecules · 2025Article
- Properties Governing Native State Entanglements and Relationships to Protein Function.Journal of molecular biology · 2025Article
- State-of-the-Art and Future Directions in Structural Proteomics.Molecular & cellular proteomics : MCP · 2025Review
- A widespread protein misfolding mechanism is differentially rescued by chaperones based on gene essentiality.bioRxiv : the preprint server for biology · 2025Article
- Non-native entanglement protein misfolding observed in all-atom simulations and supported by experimental structural ensembles.Science advances · 2025Article
- Proteins with cognition-associated structural changes in a rat model of aging exhibit reduced refolding capacity.Science advances · 2025Article
- Chaperone Dependency during Primary Protein Biogenesis Does Not Correlate with Chaperone Dependency duringbioRxiv : the preprint server for biology · 2025Article
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7 authors.
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Abstract
Stretched-exponential protein refolding kinetics, first observed decades ago, were attributed to a nonnative ensemble of structures with parallel, non-interconverting folding pathways. However, the structural origin of the large energy barriers preventing interconversion between these folding pathways is unknown. Here, we combine simulations with limited proteolysis (LiP) and cross-linking (XL) mass spectrometry (MS) to study the protein phosphoglycerate kinase (PGK). Simulations recapitulate its stretched-exponential folding kinetics and reveal that misfolded states involving changes of entanglement underlie this behavior: either formation of a nonnative, noncovalent lasso entanglement or failure to form a native entanglement. These misfolded states act as kinetic traps, requiring extensive unfolding to escape, which results in a distribution of free energy barriers and pathway partitioning. Using LiP-MS and XL-MS, we propose heterogeneous structural ensembles consistent with these data that represent the potential long-lived misfolded states PGK populates. This structural and energetic heterogeneity creates a hierarchy of refolding timescales, explaining stretched-exponential kinetics.
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