Mechanism of Hsp104/ClpB inhibition by prion curing Guanidinium hydrochloride
Research output: Contribution to journal › Journal article › Research › peer-review
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.
| Original language | English |
|---|---|
| Journal | FEBS Letters |
| Volume | 587 |
| Issue number | 6 |
| Pages (from-to) | 810-817 |
| Number of pages | 8 |
| ISSN | 0014-5793 |
| DOIs | |
| Publication status | Published - 2013 |
| Externally published | Yes |
Bibliographical note
Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
- Adenosine Triphosphate/chemistry, Binding Sites, Endopeptidase Clp, Escherichia coli/drug effects, Escherichia coli Proteins/antagonists & inhibitors, Genes, Reporter, Guanidine/chemistry, HSP70 Heat-Shock Proteins/chemistry, Heat-Shock Proteins/antagonists & inhibitors, Luciferases/genetics, Microscopy, Fluorescence, Prions/chemistry, Protein Binding, Protein Denaturation, Protein Interaction Domains and Motifs, Protein Refolding, Recombinant Proteins/antagonists & inhibitors, Saccharomyces cerevisiae/drug effects, Saccharomyces cerevisiae Proteins/antagonists & inhibitors
Research areas
ID: 257865145