Mechanism of Hsp104/ClpB inhibition by prion curing Guanidinium hydrochloride

Research output: Contribution to journalJournal articleResearchpeer-review

  • Kummer, Eva
  • Yuki Oguchi
  • Fabian Seyffer
  • Bernd Bukau
  • Axel Mogk

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 languageEnglish
JournalFEBS Letters
Issue number6
Pages (from-to)810-817
Number of pages8
Publication statusPublished - 2013
Externally publishedYes

Bibliographical note

Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    Research areas

  • 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

ID: 257865145