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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

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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.

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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.