Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors

Stefan Rothenburg, Eun Joo Seo, James S. Gibbs, Thomas E. Dever, Katharina Dittmar

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)63-70
Number of pages8
JournalNature Structural and Molecular Biology
Volume16
Issue number1
DOIs
StatePublished - Jan 2009
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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