Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors

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Abstract
PKR responds to viral infection and shuts down translation through phosphorylation of eIF2α. PKR is found to have rapidly evolved in comparison to other kinases targeting the same substrate across a broad range of vertebrate lineages. Some positively selected residues are found to confer resistance to poxviral inhibitors that mimic substrate. In addition, substituting a single residue in mouse PKR with the corresponding residue under positive selection in human PKR renders mouse PKR more resistant to K3L and vice versa, providing evidence for species-specific selection driven by beneficial mutations. Protein kinase PKR (also known as EIF2AK2) is activated during viral infection and phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2), leading to inhibition of translation and viral replication. We report fast evolution of the PKR kinase domain in vertebrates, coupled with positive selection of specific sites. Substitution of positively selected residues in human PKR with residues found in related species altered sensitivity to PKR inhibitors from different poxviruses. Species-specific differences in sensitivity to poxviral pseudosubstrate inhibitors were identified between human and mouse PKR, and these differences were traced to positively selected residues near the eIF2α binding site. Our findings indicate how an antiviral protein evolved to evade viral inhibition while maintaining its primary function. Moreover, the identified species-specific differences in the susceptibility to viral inhibitors have important implications for studying human infections in nonhuman model systems.