Protein rescue from aggregates by powerful molecular chaperone machines

Key Points When cells are exposed to stresses, proteins may misfold and aggregate. Molecular chaperones function in a myriad of cellular activities, including protein folding, remodelling and, in the case of yeast heat shock protein 104 (Hsp104) and bacterial ClpB, in the disaggregation of aggregated proteins. The oligomeric architecture of Hsp104 and ClpB is similar to other members of the HSP100 family of proteins. DnaK and Hsp70 collaborate during disaggregation with ClpB and Hsp104, respectively, through specific and direct interactions with the M-domain The M-domain of Hsp104 and ClpB modulates the ATP-dependent disaggregation activity. During the disaggregation reaction, Hsp70 and the bacterial homologue DnaK interact with the M-domain of Hsp104 and ClpB, respectively, unleashing the disaggregase activity. Determining how energy-dependent disaggregases reactivate aggregated proteins has important implications for the understanding and amelioration of aggregation-based diseases, such as Alzheimer's disease, Parkinson's disease and prion diseases. Disruption of the protein quality control system can lead to protein misfolding, inactivity and aggregation. New structural and biochemical insights into how disaggregases collaborate with co-chaperones and utilize ATP to untangle these aggregates are now being gained. This is clinically relevant, as aggregation is often linked to common neurodegenerative diseases. Protein quality control within the cell requires the interplay of many molecular chaperones and proteases. When this quality control system is disrupted, polypeptides follow pathways leading to misfolding, inactivity and aggregation. Among the repertoire of molecular chaperones are remarkable proteins that forcibly untangle protein aggregates, called disaggregases. Structural and biochemical studies have led to new insights into how these proteins collaborate with co-chaperones and utilize ATP to power protein disaggregation. Understanding how energy-dependent protein disaggregating machines function is universally important and clinically relevant, as protein aggregation is linked to medical conditions such as Alzheimer's disease, Parkinson's disease, amyloidosis and prion diseases.