Faculty Opinions recommendation of Nature and regulation of protein folding on the ribosome.
Year: 2020
Type: peer-review
Abstract: Co-translational protein folding is an essential process by which cells ensure the safe and efficient production and assembly of new proteins in their functional native states following biosynthesis on the ribosome.In this review, we describe recent progress in probing the changes during protein synthesis of the free energy landscapes that underlie co-translational folding and discuss the critical coupling between these landscapes and the rate of translation that ultimately determines the success or otherwise of the folding process.Recent developments have revealed a variety of mechanisms by which both folding and translation can be modulated or regulated, and we discuss how these effects are utilised by the cell to optimise the outcome of protein biosynthesis. How Do Proteins Fold within the Cell?Protein folding is essential to life: not only is the efficient formation of stable native structures central to biological function, but misfolding and aggregation are implicated in a wide range of pathological disorders [1].In the half century since Cyrus Levinthal's seminal observation that protein folding cannot be a random search across conformational space [102], great strides have been made in understanding the basic principles that underlie this process [2].The description of folding as a diffusive search across a free energy landscape (see Glossary) has proved to be an important development both to provide a conceptual view of the way that proteins can fold in finite times and to provide insight into the manner in which the process of folding is encoded in the sequence [3,4].However, the majority of experimental studies of protein folding have focused on the reversible folding of a relatively small number of relatively small (%100 amino acids; aa) proteins, typically following chemical or thermal denaturation [5].In contrast, the folding of larger proteins, often comprising multiple domains or subdomains, is more likely to be initiated during synthesis on the ribosome [6].Our progress in understanding the folding of such systems will be the focus of this review.As protein biosynthesis takes place within the cell, nascent polypeptide chains (NCs) are gradually extruded from the ribosomal exit tunnel, making it possible for folding to be initiated at the N terminus and to proceed in a vectorial manner before the C terminus has fully emerged from the ribosome [7][8][9].This process of co-translational folding cannot simply be described by a single free energy landscape, for the conformational space accessible to the NC expands with its length, and intermediate states may become favoured or disfavoured as it emerges.Therefore, the co-translational landscape must instead be conceptualised as a nested series of length-dependent free energy landscapes spanning increasingly large conformational spaces (Figure 1) [7,10].In this review, we discuss progress on the experimental characterisation of these landscapes, which also provides a framework to understand recently identified mechanisms through which co-translational folding may be modulated, through passive and perhaps stochastic processes, or regulated, through active interventions in the folding process.Although the experimental studies discussed here have largely been carried out on the prokaryotic ribosome, the underlying physical principles are likely to be similar for eukaryotic systems (Box 1). Describing Co-translational Protein Folding Using Free Energy LandscapesThe nested free energy landscape picture immediately highlights some novel aspects of co-translational folding relative to the folding of a full-length isolated chain.The volume of conformational space (proportional to the width of the folding surface in Figure 1) will in general be smaller for shorter polypeptide chain lengths; this feature is expected to result in more rapid folding relative to larger sequences, although the folding kinetics of individual systems will also depend on other factors such as the complexity of the fold [11].As translation (synthesis of the NC) increases the
Author: Walter Chazin
Institution: Vanderbilt University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4238971054