Protein Folding in Vivo

Abstract

Proteins are composed of linear chains of amino acids. Upon synthesis in the cell, most proteins must rapidly acquire a specific three‐dimensional structure, a process known as folding, before they can perform their various biological functions. Productive folding is often competed by aggregation, owing to the high macromolecular crowding of the cellular environment. Moreover, the process of translation increases the danger of misfolding, as incomplete nascent polypeptides are not yet able to fold into stable structures in many cases. To avoid these off‐pathway reactions, a class of proteins called molecular chaperones has evolved in all organisms. They interact with nascent or stress‐denatured polypeptides, prevent their aggregation and assist in folding and assembly processes, often in an ATP‐regulated manner. These functions are especially important in conditions of cell stress, and their failure is linked with the manifestation of numerous age‐dependent degenerative diseases. Key Concepts Molecular chaperones are proteins that mediate folding and assembly of other proteins, without being components of the final folded or assembled structures. Molecular chaperones prevent the potentially toxic aggregation of newly synthesised polypeptides during translation and when mature proteins unfold during stress conditions or ageing. Hsp70 chaperones act as a hub in the proteostasis network by assisting protein folding and conformational maintenance and by distributing client proteins to other chaperones for correct folding. The chaperonins mediate the folding of proteins with complex topologies and kinetically frustrated folding pathways.