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Dicarboxylic amino acids and glycine-betaine regulate chaperone-mediated protein-disaggregation under stress.
Active protein-disaggregation by a chaperone network composed of ClpB and DnaK + DnaJ + GrpE is essential for the recovery of stress-induced protein aggregates in vitro and in Escherichia coli cells. K-glutamate and glycine-betaine (betaine) naturally accumulate in salt-stressed cells. In addition to providing thermo-protection to native proteins, we found that these osmolytes can strongly and specifically activate ClpB, resulting in an increased efficiency of chaperone-mediated protein disaggregation. Moreover, factors that inhibited the chaperone network by impairing the stability of the ClpB oligomer, such as natural polyamines, dilution, or high salt, were efficiently counteracted by K-glutamate or betaine. The combined protective, counter-negative and net activatory effects of K-glutamate and betaine, allowed protein disaggregation and refolding under heat-shock temperatures that otherwise cause protein aggregation in vitro and in the cell. Mesophilic organisms may thus benefit from a thermotolerant osmolyte-activated chaperone mechanism that can actively rescue protein aggregates, correctly refold and maintain them in a native state under heat-shock conditions.
Adenosine Triphosphate/metabolism, Amino Acids, Dicarboxylic/metabolism, Bacterial Proteins/metabolism, Betaine/metabolism, Escherichia coli/cytology, Escherichia coli/metabolism, Escherichia coli Proteins/metabolism, Glycine/metabolism, HSP40 Heat-Shock Proteins, HSP70 Heat-Shock Proteins/metabolism, Heat-Shock Proteins/metabolism, Malate Dehydrogenase/metabolism, Molecular Chaperones/metabolism, Protein Denaturation, Protein Folding, Salts/metabolism
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