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On the Mechanism of Ezrin Activation
Dovydas Vasiliauskas1, Jeriann Beiter1, Sahithya Sridharan Iyer1
1Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, IL 60637.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
Ezrin links cell membranes to actin filaments. Binding to PI(4,5)P2 on membranes causes ezrin
Area of Science:
- Molecular Biology
- Biophysics
- Cell Biology
Background:
- Ezrin is a peripheral membrane protein crucial for cell structure.
- Ezrin links the plasma membrane to actin filaments, requiring FERM domain binding to PI(4,5)P2 and CTD phosphorylation at T567.
- The precise mechanism of ezrin activation and FERM-CTD domain dissociation remains unclear.
Purpose of the Study:
- To investigate the mechanistic steps of ezrin activation.
- To determine the thermodynamic free energy landscape of FERM-CTD dissociation.
- To elucidate the role of PI(4,5)P2 and T567 phosphorylation in ezrin function.
Main Methods:
- Enhanced sampling molecular dynamics (MD) simulations.
- Well-tempered metadynamics (WTMetaD) with a contact-map collective variable.
- Thermodynamic free energy calculations.
Main Results:
- PI(4,5)P2 binding to ezrin's FERM domain triggers conformational changes that destabilize the FERM-CTD interface.
- FERM-CTD dissociation is primarily hindered by F3-CTD interactions and occurs with a moderate free energy barrier.
- T567 phosphorylation impedes FERM-CTD reassociation by reducing the dissociation energy barrier.
Conclusions:
- Ezrin activation involves spontaneous FERM-CTD dissociation upon PI(4,5)P2 binding.
- The nonphosphorylated CTD dissociates readily, allowing ezrin to interact with other proteins like EBP50.
- This provides a revised mechanistic view of ezrin activation and its regulation.
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