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Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90

Author

Listed:
  • Sophie L. Mader

    (Technical University of Munich)

  • Abraham Lopez

    (Technical University of Munich
    Helmholtz Zentrum München)

  • Jannis Lawatscheck

    (Technical University of Munich)

  • Qi Luo

    (Technical University of Munich
    Zhejiang University)

  • Daniel A. Rutz

    (Technical University of Munich)

  • Ana P. Gamiz-Hernandez

    (Technical University of Munich
    Stockholm University)

  • Michael Sattler

    (Technical University of Munich
    Helmholtz Zentrum München)

  • Johannes Buchner

    (Technical University of Munich)

  • Ville R. I. Kaila

    (Technical University of Munich
    Stockholm University)

Abstract

The heat shock protein 90 (Hsp90) is a molecular chaperone that employs the free energy of ATP hydrolysis to control the folding and activation of several client proteins in the eukaryotic cell. To elucidate how the local ATPase reaction in the active site couples to the global conformational dynamics of Hsp90, we integrate here large-scale molecular simulations with biophysical experiments. We show that the conformational switching of conserved ion pairs between the N-terminal domain, harbouring the active site, and the middle domain strongly modulates the catalytic barrier of the ATP-hydrolysis reaction by electrostatic forces. Our combined findings provide a mechanistic model for the coupling between catalysis and protein dynamics in Hsp90, and show how long-range coupling effects can modulate enzymatic activity.

Suggested Citation

  • Sophie L. Mader & Abraham Lopez & Jannis Lawatscheck & Qi Luo & Daniel A. Rutz & Ana P. Gamiz-Hernandez & Michael Sattler & Johannes Buchner & Ville R. I. Kaila, 2020. "Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15050-0
    DOI: 10.1038/s41467-020-15050-0
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    Cited by:

    1. Faustine Henot & Elisa Rioual & Adrien Favier & Pavel Macek & Elodie Crublet & Pierre Josso & Bernhard Brutscher & Matthias Frech & Pierre Gans & Claire Loison & Jerome Boisbouvier, 2022. "Visualizing the transiently populated closed-state of human HSP90 ATP binding domain," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Stefan Riedl & Ecenaz Bilgen & Ganesh Agam & Viivi Hirvonen & Alexander Jussupow & Franziska Tippl & Maximilian Riedl & Andreas Maier & Christian F. W. Becker & Ville R. I. Kaila & Don C. Lamb & Johan, 2024. "Evolution of the conformational dynamics of the molecular chaperone Hsp90," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Jonathan Schubert & Andrea Schulze & Chrisostomos Prodromou & Hannes Neuweiler, 2021. "Two-colour single-molecule photoinduced electron transfer fluorescence imaging microscopy of chaperone dynamics," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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