Unraveling the Mechanism of Protein Disaggregation Through a ClpB-DnaK Interaction

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Science  01 Mar 2013:
Vol. 339, Issue 6123, pp. 1080-1083
DOI: 10.1126/science.1233066

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Dissecting Disaggregation

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.


HSP-100 protein machines, such as ClpB, play an essential role in reactivating protein aggregates that can otherwise be lethal to cells. Although the players involved are known, including the DnaK/DnaJ/GrpE chaperone system in bacteria, details of the molecular interactions are not well understood. Using methyl–transverse relaxation–optimized nuclear magnetic resonance spectroscopy, we present an atomic-resolution model for the ClpB-DnaK complex, which we verified by mutagenesis and functional assays. ClpB and GrpE compete for binding to the DnaK nucleotide binding domain, with GrpE binding inhibiting disaggregation. DnaK, in turn, plays a dual role in both disaggregation and subsequent refolding of polypeptide chains as they emerge from the aggregate. On the basis of a combined structural-biochemical analysis, we propose a model for the mechanism of protein aggregate reactivation by ClpB.

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