The ribosome lowers the entropic penalty of protein folding

• 成果类型: Article
• 署名作者: Streit, Julian O.; Bukvin, Ivana V.; Chan, Sammy H. S.; Bashir, Shahzad; Woodburn, Lauren F.; Wlodarski, Tomasz; Figueiredo, Angelo Miguel; Jurkeviciute, Gabija; Sidhu, Haneesh K.; Hornby, Charity R.; Waudby, Christopher A.; Cabrita, Lisa D.; Cassaignau, Anais M. E.; Christodoulou, John
• 署名单位: University of London; Birkbeck University London
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3685
• DOI: 10.1038/s41586-024-07784-4
• 发表日期: 2024-09-05
• 页码: 232-+
• 关键词: molecular-dynamics; paramagnetic relaxation; cotranslational ubiquitination; conformational entropy; diffusion measurements; immunoglobulin domain; thermodynamic model; hydrodynamic radius; secondary structure; structural basis

摘要

Most proteins fold during biosynthesis on the ribosome(1), and co-translational folding energetics, pathways and outcomes of many proteins have been found to differ considerably from those in refolding studies(2-10). The origin of this folding modulation by the ribosome has remained unknown. Here we have determined atomistic structures of the unfolded state of a model protein on and off the ribosome, which reveal that the ribosome structurally expands the unfolded nascent chain and increases its solvation, resulting in its entropic destabilization relative to the peptide chain in isolation. Quantitative F-19 NMR experiments confirm that this destabilization reduces the entropic penalty of folding by up to 30 kcal mol(-1) and promotes formation of partially folded intermediates on the ribosome, an observation that extends to other protein domains and is obligate for some proteins to acquire their active conformation. The thermodynamic effects also contribute to the ribosome protecting the nascent chain from mutation-induced unfolding, which suggests a crucial role of the ribosome in supporting protein evolution. By correlating nascent chain structure and dynamics to their folding energetics and post-translational outcomes, our findings establish the physical basis of the distinct thermodynamics of co-translational protein folding.