Cells employ sophisticated quality control systems to ensure that cellular proteins perform their intended functions. Under stress conditions, however, proteins folding can start to go wrong, causing the accumulation of misfolded proteins and formation of toxic protein aggregates. Hsp104/ClpB molecular chaperones can help reverse these toxic effects by forcibly untangling protein aggregates and allowing the client proteins to refold into their native states.
The majority of proteins depend on a well-defined three-dimensional structure to obtain their functionality. In order to prevent misfolding, aggregation, and the generation of toxic species, the process of protein folding in the cell is often guided by molecular chaperones. These complex protein networks either interact with substrate polypeptides to help them fold; unfold misfolded species; resolve aggregates; or deliver substrates to proteolysis.
Protein disaggregases hold the potential to reverse protein aggregation and amyloid fibril formation – conditions that have been identified in an increasing number of debilitating, and ultimately fatal neurodegenerative disorders. In yeast, bacteria, and plants, a hexameric Hsp104/ClpB can solubilize these disordered aggregates and amyloids, however, curiously, metazoa lack an Hsp104 homolog. Instead, our cells employ a different, less understood machinery to refold protein aggregates – a chaperone system comprised of Hsp110, Hsp70, and Hsp40s.