Review: Mechanisms of disaggregation and refolding of stable protein aggregates by molecular chaperones

Anat Peres Ben-Zvi*, Pierre Goloubinoff

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish
Pages (from-to)84-93
Number of pages10
JournalJournal of Structural Biology
Issue number2
StatePublished - 2001
Externally publishedYes


  • Aggregate solubilization
  • ClpB
  • DnaK
  • GroEL
  • Heat shock
  • Malate dehydrogenase
  • Stress


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