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Structural Basis for Mechanical Coupling in Hsp90: Hinge Flexibility Coordinates ATP Gate Closure and β-Strap Release
Breanna Magnan1, Paul LaPointe2, Leo Spyracopoulos1
1Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Biochemistry
|June 3, 2026
Summary
The ATP gate hinge in Heat Shock Protein 90 (Hsp90) acts as a mechanical switch, controlling its conformational changes and client protein remodeling. This hinge flexibility is crucial for Hsp90 function and regulation.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- Heat Shock Protein 90 (Hsp90) is a vital molecular chaperone.
- Hsp90 facilitates protein folding and stability through ATP-dependent conformational changes.
- Coordination between the ATP gate and N-terminal β-strap is essential for Hsp90's catalytic cycle.
Purpose of the Study:
- To identify the key mechanical element mediating structural coupling in the Hsp90 ATP cycle.
- To elucidate the role of the ATP gate hinge in Hsp90 conformational dynamics.
- To understand how local hinge dynamics influence Hsp90 dimer regulation.
Main Methods:
- Site-specific backbone restriction.
- 19F nuclear magnetic resonance (NMR) spectroscopy.
- Molecular dynamics (MD) simulations.
Main Results:
- The C-terminal hinge of the ATP gate (G123) was identified as a critical mechanical element.
- Hinge plasticity is essential for Hsp90 to transition to its closed state.
- Restricting hinge flexibility prevents Hsp90 closure and decouples the β-strap from the ATP gate.
- Hinge rigidity controls intersubunit communication in Hsp90 heterodimers.
Conclusions:
- The ATP gate hinge acts as a mechanical switch governing Hsp90's global conformational state.
- Local backbone dynamics at the hinge drive long-range regulation within the Hsp90 dimer.
- These findings provide a structural basis for Hsp90 activation and regulation.
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