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Review
. 2007 Feb;32(2):57-62.
doi: 10.1016/j.tibs.2006.12.003. Epub 2006 Dec 29.

Activation of PKR: an open and shut case?

James L Cole  1
Affiliations
Review

Activation of PKR: an open and shut case?

James L Cole. Trends Biochem Sci. 2007 Feb.

Abstract

The double-stranded (ds) RNA-activated protein kinase, PKR, has a key role in the innate immunity response to viral infection in higher eukaryotes. PKR contains an N-terminal dsRNA-binding domain and a C-terminal kinase domain. In the prevalent autoinhibition model for PKR activation, dsRNA binding induces a conformational change that leads to the release of the dsRNA-binding domain from the kinase, thus relieving the inhibition of the latent enzyme. Structural and biophysical data now favor a model whereby dsRNA principally functions to induce dimerization of PKR via the kinase domain. This dimerization model has implications for other PKR regulatory mechanisms and represents a new structural paradigm for control of protein kinase activity.

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Figures

Figure 1
Figure 1
PKR domains and their interactions. (a) Domain organization and structures. The N-terminal regulatory domain is comprised of two dsRNA binding motifs, dsRBM1 and dsRBM2 connected by an unstructured linker. Each of these motifs adopts the canonical αβββα fold in the NMR structure of dsRNA binding domain (1QU6). In the crystal structure of a complex of the PKR kinase domain and eIF2α (2A1A), the kinase domain has the typical bilobal structure observed in other eukaryotic protein kinases and dimerizes via the N-terminal lobe (note, the substrate eIF2α was omitted from the figure for clarity). (b) Schematic diagram of PKR. The color scheme corresponds to (a). (c) Autoinhibition model for PKR. The interaction of dsRBM2 with the kinase domain blocks activity of latent PKR. Binding to dsRNA activates PKR by removing dsRBM2 from kinase. (d) Dimerization model for PKR activation by dsRNA. Binding to dsRNA induces PKR dimerization via the kinase domain, resulting in activation.
Figure 2
Figure 2
Structural analysis of PKR dimerization. (a) Comparison of the dimer structures of the kinase domains of PKR, PknE and GCN2. PKR (green) and M. tuberculosis PknE (aqua) dimerize in a similar parallel orientation using an interface on the back of the N-lobe. Although S. cerevisiae GCN2 (orange/grey) dimerizes via a similar interface, the monomers are anti-parallel. The two subunits of GCN2 are shown in different colors for clarity. (b) Helix αC links the dimerization interface to the nucleotide binding site and the activation loop. Helix αC is colored purple, residues comprising the dimer interface are colored grey and the activation loop is colored blue. Glu308 of helix αC interacts with Lys296, which orients the α and β phosphates of AMP-PNP. Two basic residues from helix αC, Lys304 and Arg307, form salt bridges with the negatively charged phosphate moiety of phospho-Thr446. The figure was generated using the following coordinates: PKR:AMP-PNP:eIF2α, 2A19; PknE, 2H34; GCN2, 1ZYC.
Figure 2
Figure 2
Structural analysis of PKR dimerization. (a) Comparison of the dimer structures of the kinase domains of PKR, PknE and GCN2. PKR (green) and M. tuberculosis PknE (aqua) dimerize in a similar parallel orientation using an interface on the back of the N-lobe. Although S. cerevisiae GCN2 (orange/grey) dimerizes via a similar interface, the monomers are anti-parallel. The two subunits of GCN2 are shown in different colors for clarity. (b) Helix αC links the dimerization interface to the nucleotide binding site and the activation loop. Helix αC is colored purple, residues comprising the dimer interface are colored grey and the activation loop is colored blue. Glu308 of helix αC interacts with Lys296, which orients the α and β phosphates of AMP-PNP. Two basic residues from helix αC, Lys304 and Arg307, form salt bridges with the negatively charged phosphate moiety of phospho-Thr446. The figure was generated using the following coordinates: PKR:AMP-PNP:eIF2α, 2A19; PknE, 2H34; GCN2, 1ZYC.
Figure 3
Figure 3
Model for PKR activation. PKR exists in an open conformation (i) in a weak monomer-dimer equilibrium. Dimerization is induced by binding to dsRNA (ii) or at high protein concentration (iii), producing an enzyme form competent to undergo autophosphorylation. ATP is able to bind readily to both monomeric and dimeric PKR. The autophosphorylated dimer dissociates readily from dsRNA (iv). The PKR dimer is stabilized by phosphorylation (v) and represents the enzyme form competent to phosphorylate eIF2α. The PKR dimerization dissociation constants were obtained from reference [24] and the ATP dissociation constants were obtained from reference [22].
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