PMID:23416293
| Citation |
Kummer, E, Oguchi, Y, Seyffer, F, Bukau, B and Mogk, A (2013) Mechanism of Hsp104/ClpB inhibition by prion curing Guanidinium hydrochloride. FEBS Lett. 587:810-7 |
|---|---|
| Abstract |
The Saccharomyces cerevisiae AAA+ protein Hsp104 and its Escherichia coli counterpart ClpB cooperate with Hsp70 chaperones to refold aggregated proteins and fragment prion fibrils. Hsp104/ClpB activity is regulated by interaction of the M-domain with the first ATPase domain (AAA-1), controlling ATP turnover and Hsp70 cooperation. Guanidinium hydrochloride (GdnHCl) inhibits Hsp104/ClpB activity, leading to prion curing. We show that GdnHCl binding exerts dual effects on Hsp104/ClpB. First, GdnHCl strengthens M-domain/AAA-1 interaction, stabilizing Hsp104/ClpB in a repressed conformation and abrogating Hsp70 cooperation. Second, GdnHCl inhibits continuous ATP turnover by AAA-1. These findings provide the mechanistic basis for prion curing by GdnHCl. |
| Links |
PubMed Online version:10.1016/j.febslet.2013.02.011 |
| Keywords |
Adenosine Triphosphate/chemistry; Adenosine Triphosphate/metabolism; Binding Sites; Escherichia coli/drug effects; Escherichia coli/genetics; Escherichia coli/metabolism; Escherichia coli Proteins/antagonists & inhibitors; Escherichia coli Proteins/genetics; Escherichia coli Proteins/metabolism; Genes, Reporter; Guanidine/chemistry; Guanidine/pharmacology; HSP70 Heat-Shock Proteins/chemistry; HSP70 Heat-Shock Proteins/genetics; HSP70 Heat-Shock Proteins/metabolism; Heat-Shock Proteins/antagonists & inhibitors; Heat-Shock Proteins/genetics; Heat-Shock Proteins/metabolism; Luciferases/genetics; Microscopy, Fluorescence; Prions/chemistry; Prions/metabolism; Protein Binding; Protein Denaturation; Protein Interaction Domains and Motifs; Protein Refolding; Recombinant Proteins/antagonists & inhibitors; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Saccharomyces cerevisiae/drug effects; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/metabolism; Saccharomyces cerevisiae Proteins/antagonists & inhibitors; Saccharomyces cerevisiae Proteins/genetics; Saccharomyces cerevisiae Proteins/metabolism |
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