Machinery to Reverse Irreversible Aggregates

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Science  01 Mar 2013:
Vol. 339, Issue 6123, pp. 1040-1041
DOI: 10.1126/science.1236012

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Protein misfolding and aggregation would drastically shorten the life of cells were it not for the molecular chaperones that prevent these damaging processes (1). In vitro, aggregation is irreversible under physiological conditions. Remarkably, the cells of bacteria, plants, and fungi have evolved machinery to neatly extract polypeptide chains from large aggregates and refold them to the native state, with little specificity for protein sequence or fold (24). Although the components of this machinery are well known, an understanding of how they accomplish disaggregation has been elusive. Several recent studies (58), including one by Rosenzweig et al. (9) on page 1080 of this issue, identify interaction sites within a chaperone system consisting of an Hsp70 chaperone (bacterial DnaK) and a protein-remodeling adenosine triphosphatase (ATPase) of the AAA+ family (bacterial ClpB or yeast Hsp104). Nuclear magnetic resonance (NMR), crystallographic, and biochemical studies reveal a series of molecular toggles that control polypeptide aggregate binding, extraction, threading, and refolding by this bichaperone system.