期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：47
页码：13402-13407
DOI：10.1073/pnas.1610272113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceA fundamental question in biology is how the biophysical parameters describing protein folding in vitro are altered during cotranslational folding. Because protein synthesis is slow, nascent chains can fold cotranslationally while still tethered to the ribosome and before the entire protein has emerged. Here we examine the effects of ribosomal tethering on protein stability and how that stability is modulated by the distance away from the ribosomes active site. We develop a quantitative assay for measuring protein stability on stalled nascent chains and find that the ribosome destabilizes nascent chains. This destabilization may play a key role in ensuring folding fidelity by helping the nascent chain avoid partially folded kinetic traps before the entire chain has been synthesized. Accurate protein folding is essential for proper cellular and organismal function. In the cell, protein folding is carefully regulated; changes in folding homeostasis (proteostasis) can disrupt many cellular processes and have been implicated in various neurodegenerative diseases and other pathologies. For many proteins, the initial folding process begins during translation while the protein is still tethered to the ribosome; however, most biophysical studies of a proteins energy landscape are carried out in isolation under idealized, dilute conditions and may not accurately report on the energy landscape in vivo. Thus, the energy landscape of ribosome nascent chains and the effect of the tethered ribosome on nascent chain folding remain unclear. Here we have developed a general assay for quantitatively measuring the folding stability of ribosome nascent chains, and find that the ribosome exerts a destabilizing effect on the polypeptide chain. This destabilization decreases as a function of the distance away from the peptidyl transferase center. Thus, the ribosome may add an additional layer of robustness to the protein-folding process by avoiding the formation of stable partially folded states before the protein has completely emerged from the ribosome.
