Review: mechanisms of disaggregation and refolding of stable protein aggregates by molecular chaperones.
Molecular chaperones are essential for the correct folding of proteins in the cell under physiological and stress conditions. Two activities have been traditionally attributed to molecular chaperones: (1) preventing aggregation of unfolded polypeptides and (2) assisting in the correct refolding of chaperone-bound denatured polypeptides. We discuss here a novel function of molecular chaperones: catalytic solubilization and refolding of stable protein aggregates. In Escherichia coli, disaggregation is carried out by a network of ATPase chaperones consisting of a DnaK core, assisted by the cochaperones DnaJ, GrpE, ClpB, and GroEL-GroES. We suggest a sequential mechanism in which (a) ClpB exposes new DnaK-binding sites on the surface of the stable protein aggregates; (b) DnaK binds the aggregate surfaces and, by doing so, melts the incorrect hydrophobic associations between aggregated polypeptides; (c) ATP hydrolysis and DnaK release allow local intramolecular refolding of native domains, leading to a gradual weakening of improper intermolecular links; (d) DnaK and GroEL complete refolding of solubilized polypeptide chains into native proteins. Thus, active disaggregation by the chaperone network can serve as a central cellular tool for the recovery of native proteins from stress-induced aggregates and actively remove disease-causing toxic aggregates, such as polyglutamine-rich proteins, amyloid plaques, and prions.
Ben-Zvi
A P
AP
Department of Plant Sciences, A Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
Goloubinoff
P
P
D000251:Adenosine Triphosphatases / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D006801:Humans; D046911:Macromolecular Substances; D018832:Molecular Chaperones / Q000494:pharmacology / Q000502:physiology*; D017510:Protein Folding; D020673:Protein Renaturation / Q000187:drug effects*
D046911:Macromolecular Substances; D018832:Molecular Chaperones; D000251:Adenosine Triphosphatases