title: Review: mechanisms of disaggregation and refolding of stable protein aggregates by molecular chaperones.
abstract: 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.
authors.affiliation: Department of Plant Sciences, A Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
authors.forename: A P
authors.initials: AP
authors.lastname: Ben-Zvi
authors.forename: P
authors.initials: P
authors.lastname: Goloubinoff
mesh_terms: 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*
chemical_list: D046911:Macromolecular Substances; D018832:Molecular Chaperones; D000251:Adenosine Triphosphatases