title: Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors.
abstract: Protein kinase PKR (also known as EIF2AK2) is activated during viral infection and phosphorylates the alpha 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 eIF2alpha 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.
authors.affiliation: Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA. rothenst@mail.nih.gov
authors.forename: Stefan
authors.initials: S
authors.lastname: Rothenburg
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Seo
authors.forename: James S
authors.initials: JS
authors.lastname: Gibbs
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Dever
authors.forename: Katharina
authors.initials: K
authors.lastname: Dittmar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004279:DNA, Viral / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D010802:Phylogeny; D011487:Protein Conformation; D012367:RNA, Viral / Q000378:metabolism; D013379:Substrate Specificity; D014764:Viral Proteins / Q000378:metabolism; D019892:eIF-2 Kinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004279:DNA, Viral; D015852:Eukaryotic Initiation Factor-2; D012367:RNA, Viral; D014764:Viral Proteins; D019892:eIF-2 Kinase