Chaperone machines for protein folding, unfolding and disaggregation

Molecular chaperones have key roles in protein quality control and recovery from stress conditions. They assist folding and unfolding and prevent or reverse aggregation of a wide range of substrates, but their actions decline with age, leading to late onset misfolding diseases.The major chaperone systems of the cell, namely heat shock protein 60 (HSP60), HSP70, HSP90 and HSP100, use the energy of ATP binding and hydrolysis to carry out their actions, which include stabilizing non-native proteins, unfolding misfolded proteins or folded proteins targeted for proteolysis as well as providing conditions that are favourable for folding.HSP70 and HSP90 are highly interactive, open structures with many exposed binding sites for co-chaperones that regulate their functions in various of biological pathways. By contrast, HSP60 and HSP100 are self-contained, with internalized active sites and few cooperating partners.Chaperones are extremely flexible and dynamic machines. In order to act on their substrates, their domains rotate up to 100° and are displaced by up to 50 Å or more.ATP binding and hydrolysis influence the accessibility and dynamics of binding sites for non-native proteins. For example, the lid subdomain of the substrate-binding domain in HSP70 is fully opened upon interaction with the ATPase domain, whereas HSP60 converts an open ring into an enclosed container for protein folding.