Hsp70 proteins bind Hsp100 regulatory M domains to activate AAA+ disaggregase at aggregate surfaces

Research output: Contribution to journalJournal articleResearchpeer-review

  • Fabian Seyffer
  • Kummer, Eva
  • Yuki Oguchi
  • Juliane Winkler
  • Mohit Kumar
  • Regina Zahn
  • Victor Sourjik
  • Bernd Bukau
  • Axel Mogk

Bacteria, fungi and plants rescue aggregated proteins using a powerful bichaperone system composed of an Hsp70 chaperone and an Hsp100 AAA+ disaggregase. In Escherichia coli, the Hsp70 chaperone DnaK binds aggregates and targets the disaggregase ClpB to the substrate. ClpB hexamers use ATP to thread substrate polypeptides through the central pore, driving disaggregation. How ClpB finds DnaK and regulates threading remains unclear. To dissect the disaggregation mechanism, we separated these steps using primarily chimeric ClpB-ClpV constructs that directly recognize alternative substrates, thereby obviating DnaK involvement. We show that ClpB has low intrinsic disaggregation activity that is normally repressed by the ClpB middle (M) domain. In the presence of aggregate, DnaK directly binds M-domain motif 2, increasing ClpB ATPase activity to unleash high ClpB threading power. Our results uncover a new function for Hsp70: the coupling of substrate targeting to AAA+ chaperone activation at aggregate surfaces.

Original languageEnglish
JournalNature Structural & Molecular Biology
Issue number12
Pages (from-to)1347-55
Number of pages9
Publication statusPublished - 2012
Externally publishedYes

    Research areas

  • HSP70 Heat-Shock Proteins/metabolism, Protein Binding

ID: 257865233