Protein misfolding involving entanglements providesa structural explanation for the origin of stretched-exponential refolding kinetics.

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Tác giả: Stephen D Fried, Yang Jiang, Edward P O'Brien, Piyoosh Sharma, Ian Sitarik, Hyebin Song, Yingzi Xia

Ngôn ngữ: eng

Ký hiệu phân loại: 809.008 History and description with respect to kinds of persons

Thông tin xuất bản: United States : Science advances , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 707598

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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