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Dimerization Promotes PKR Activation by Modulating Energetics of αC Helix Conversion between Active and Inactive
Aaron G Feinstein1, James L Cole1,2, Eric R May1
1Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269, United States.
The Journal of Physical Chemistry. B
|October 3, 2024
Summary
Protein kinase R (PKR) activation, crucial for innate immunity, involves back-to-back dimerization. Molecular dynamics reveal this dimerization stabilizes a catalytically active PKR conformation, elucidating its antiviral defense mechanism.
Area of Science:
- Molecular Biology
- Immunology
- Structural Biology
Background:
- Protein kinase R (PKR) is a key component of the innate immune system.
- PKR activation by viral dsRNA initiates antiviral responses by inhibiting protein synthesis.
- The precise mechanism of PKR activation via kinase domain dimerization remains unclear.
Purpose of the Study:
- To investigate the structural and energetic basis of PKR activation.
- To elucidate the role of the αC helix in PKR dimerization and activation.
- To map allosteric communication pathways within the PKR dimer.
Main Methods:
- All-atom equilibrium and enhanced sampling molecular dynamics simulations.
- Window-exchange umbrella sampling to compute free-energy profiles.
- Linear mutual information analysis for allosteric communication.
Main Results:
- Back-to-back dimerization stabilizes a catalytically competent conformation of PKR.
- Hydrophobic residues at the dimer interface stabilize the active αC helix conformation.
- Allosteric communication pathways were identified between N-lobes, the dimer interface, and the αC helix.
Conclusions:
- PKR activation is structurally driven by back-to-back dimerization.
- The αC helix is a critical hub for signal integration and kinase activation.
- Understanding PKR's activation mechanism provides insights into antiviral innate immunity.
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