2025-03-14 ペンシルベニア州立大学(PennState)
<関連情報>
- https://www.psu.edu/news/eberly-college-science/story/protein-accidentally-lassos-itself-helping-explain-unusual-refolding
- https://www.science.org/doi/10.1126/sciadv.ads7379
タンパク質のミスフォールディングに絡まることで、指数関数的なリフォールディングキネティクスの起源の構造的説明が可能になる Protein misfolding involving entanglements provides a structural explanation for the origin of stretched-exponential refolding kinetics
Yang Jiang, Yingzi Xia, Ian Sitarik, Piyoosh Sharma, […], and Edward P. O’Brien
Science Advances Published:14 Mar 2025
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.
