The past two decades have witnessed a paradigm shift in our understanding of cellular protein folding. While the three-dimensional structures of functional proteins are determined by their amino acid sequences, as originally demonstrated by Anfinsen, it has become clear that within the crowded environment of cells many proteins depend on so-called molecular chaperones to reach their folded states 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. <br><br>
Once folded, many proteins continue to require chaperones to retain their functional states, particularly under conditions of cell stress. Failure of the chaperone machinery to maintain the conformational stability of the cellular proteome may facilitate the manifestation of diseases in which proteins misfold and are deposited as aggregates, such as Parkinson s and Huntington s disease. A decline in chaperone capacity occurs during aging, explaining why age is the major risk factor of neurodegenerative disease. Motivated by the desire to find a cure for these debilitating diseases, researchers are now searching for drugs that can activate the chaperone system, thereby delaying the onset of aggregation diseases and prolonging the healthy human lifespan.