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

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Science  07 Feb 2013:
1233066
DOI: 10.1126/science.1233066

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Abstract

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, which in bacteria include the DnaK/DnaJ/GrpE chaperone system, 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. Based on a combined structural-biochemical analysis, we propose a model for the mechanism of protein aggregate reactivation by ClpB.

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