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

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 extensi

SUBMITTER: Jiang Y 

PROVIDER: S-EPMC11908495 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature