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Structural Basis of Protein Kinase R Autophosphorylation

Christopher B Mayo, Heidi Erlandsen, David J Mouser

    Biochemistry
    |June 28, 2019
    PubMed

    Insights

    The RNA-activated protein kinase, PKR, forms a novel front-to-front dimer structure, enabling trans-autophosphorylation crucial for innate immunity against viral infections.

    Area of Science:

    • Biochemistry
    • Molecular Biology
    • Immunology

    Background:

    • RNA-activated protein kinase (PKR) mediates innate immunity.
    • Viral dsRNA triggers PKR dimerization and autophosphorylation.
    • The canonical PKR kinase domain dimer arrangement hinders intermolecular phosphorylation.

    Purpose of the Study:

    • To elucidate the structural basis of PKR autophosphorylation.
    • To resolve the dilemma of intermolecular phosphorylation in PKR dimers.
    • To propose a mechanism for PKR activation and function.

    Main Methods:

    • X-ray crystallography of PKR kinase domain structures.
    • Mutational analysis of PKR interfaces.
    • Molecular dynamics simulations.

    Main Results:

    • PKR kinase domains form a unique front-to-front dimer via activation segment exchange.
    • This novel interface is critical for PKR activation.
    • Simulations show dynamic activation segments facilitating phosphoryl transfer.

    Conclusions:

    • A new model for PKR activation involving back-to-back and front-to-front dimerization is proposed.
    • This mechanism explains how PKR achieves trans-autophosphorylation.
    • The findings may apply to related kinases involved in eIF2α phosphorylation.

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