Molecular Chaperones in Cellular Protein Folding: Mechanisms and Pathways

Abstract

The past two decades have witnessed a paradigm shift in our understanding of protein folding in the cell. While the three‐dimensional structures of functional proteins are determined by their amino acid sequences, it has become clear that in the crowded cellular environment many proteins depend on molecular chaperones to fold efficiently and at a biologically relevant time scale. Assistance of protein folding is provided by different types of chaperone which act to prevent misfolding and aggregation, often in an ATP‐dependent mechanism. In the cytosol, nascent chain‐binding chaperones, including Trigger factor and Hsp70, stabilize elongating polypeptide chains on ribosomes in a non‐aggregated state. Folding is then achieved either on controlled chain release from these factors or following polypeptide transfer to downstream chaperones, such as the cylindrical chaperonins, GroEL and TRiC. The latter provide nano‐compartments for single protein molecules to fold in isolation, unimpaired by aggregation.Once folded, many proteins continue to require chaperones to retain their functional state, particularly under conditions of cell stress. Failure of the chaperone network to maintain proteostasis, i.e. the conformational integrity of the cellular proteome, may facilitate the manifestation of pathological states, such as Parkinson's and Huntington's disease, in which proteins misfold and are deposited as aggregates. A decline in proteostasis capacity occurs during aging, presumably explaining why age is a major risk factor of neurodegeneration.I will discuss recent findings from mechanistic and systems‐level studies to understand the organisation of the cellular chaperone network.