Unraveling the Mechanism of Protein Disaggregation Through a ClpB-DnaK Interaction
The excessive accumulation of misfolded protein aggregates can overwhelm the cell's "quality control" machinery, leading to cell death. The yeast Hsp104 protein and its bacterial homolog ClpB are molecular chaperones that can "rescue" aggregated proteins by coupling the force generated from adenosine triphosphate hydrolysis to the progressive unfolding and threading of extended polypeptide segments through axial channels in these large molecular machines. Unfolded polypeptides emerging from the channel are refolded with the aid of a second chaperone system, DnaK/DnaJ/GrpE. DnaK also plays an important role in bringing regions of polypeptides within aggregates to ClpB to begin the solubilization process. Rosenzweig et al. (p. 1080, published online 7 February; see the Perspective by Saibil) describe a nuclear magnetic resonance–derived structure of the ClpB-DnaK complex, and verified it through mutagenesis and functional assays. The work clarifies the roles of each of the molecular players in the disaggregation reaction and provides a structural basis for the DnaK-ClpB interaction.