Dimerization Promotes PKR Activation by Modulating Energetics of αC Helix Conversion between Active and Inactive Conformations.

ABSTRACT: Protein kinase R (PKR) functions in the eukaryotic innate immune system as a first-line defense against viral infections. PKR binds viral dsRNA, leading to autophosphorylation and activation. In its active state, PKR can phosphorylate its primary substrate, eIF2α, which blocks the initiation of translation in the infected cell. It has been established that PKR activation occurs when the kinase domain dimerizes in a back-to-back configuration. However, the mechanism by which dimerization leads to enzymatic activation is not fully understood. Here, we investigate the structural mechanistic basis and energy landscape for PKR activation, with a focus on the αC helix─a kinase activation and signal integration hub─using all-atom equilibrium and enhanced sampling molecular dynamics simulations. B

SUBMITTER: Feinstein AG 

PROVIDER: S-EPMC11457141 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature