Post-Translational Modification as an Allosteric Switch in Hsp90: How Dual Phosphorylation Locks Chaperone Complexes
Giorgio Bonollo1, Benedetto Roncati1, Luca Torielli1
1Department of Chemistry, University of Pavia, Via Taramelli 12, 27100, Pavia, Italy.
The Journal of Physical Chemistry Letters
|July 6, 2026
Summary
Dual phosphorylation of heat shock protein 90 beta (Hsp90β) acts as a molecular clamp. This stabilizes interactions crucial for epichaperome formation, offering therapeutic targets for diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Heat shock protein 90 beta (Hsp90β) is a crucial molecular chaperone.
- Post-translational modifications regulate Hsp90β function and client interactions.
- Hsp90β plays a role in disease pathogenesis and is a therapeutic target.
Purpose of the Study:
- To elucidate the atomistic mechanism of Hsp90β regulation by dual phosphorylation at Ser226/Ser255.
- To understand how these modifications stabilize Hsp90β interaction states.
- To explore the implications for epichaperome formation and disease biology.
Main Methods:
- Multimicrosecond molecular dynamics (MD) simulations were employed.
- Analysis focused on structural rigidity and allosteric communication within Hsp90β.
- Investigated the stabilization of cochaperone-client interfaces.
Main Results:
- Dual phosphorylation at Ser226/Ser255 acts as a molecular clamp, rigidifying Hsp90β.
- Phosphorylation propagates allosteric changes to distal domains.
- Stabilization of cochaperone-client interfaces promotes epichaperome formation.
Conclusions:
- Post-translational modifications like dual phosphorylation are key regulators of Hsp90β.
- Provides an atomistic understanding of Hsp90β stabilization for epichaperome formation.
- Highlights Hsp90β phosphorylation as a potential therapeutic strategy for diseases.
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