Chaperone‐assisted protein folding in health and disease

Within the crowded environment of the cell many proteins depend on molecular chaperones for efficient folding. Assistance of protein folding is provided by several 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 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 chaperonin GroEL, which provides a compartment for single protein molecules to fold in isolation. Recent work indicates that these chaperonin nano‐cages not only function to prevent aggregation but also to modulate the energy landscape of the folding process, thereby accelerating folding for certain proteins. The cytosolic chaperone machinery also has an important role in controlling protein misfolding and aggregation in the context of neurodegenerative disorders such as Parkinson's and Huntington's disease (HD). Specifically, Hsp70 and chaperonins can cooperate to prevent the formation of toxic protein oligomers. A reduction in the general capacity of the chaperone system during aging may be critical in the manifestation of these late‐onset diseases, suggesting up‐regulation of chaperones as a possible therapeutic strategy.