title: Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR.
abstract: In response to binding viral double-stranded RNA byproducts within a cell, the RNA-dependent protein kinase PKR phosphorylates the alpha subunit of the translation initiation factor eIF2 on a regulatory site, Ser51. This triggers the general shutdown of protein synthesis and inhibition of viral propagation. To understand the basis for substrate recognition by and the regulation of PKR, we determined X-ray crystal structures of the catalytic domain of PKR in complex with eIF2alpha. The structures reveal that eIF2alpha binds to the C-terminal catalytic lobe while catalytic-domain dimerization is mediated by the N-terminal lobe. In addition to inducing a local unfolding of the Ser51 acceptor site in eIF2alpha, its mode of binding to PKR affords the Ser51 site full access to the catalytic cleft of PKR. The generality and implications of the structural mechanisms uncovered for PKR to the larger family of four human eIF2alpha protein kinases are discussed.
authors.affiliation: Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Arvin C
authors.initials: AC
authors.lastname: Dar
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Dever
authors.forename: Frank
authors.initials: F
authors.lastname: Sicheri
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D019281:Dimerization; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D019892:eIF-2 Kinase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D012330:RNA, Double-Stranded; D019892:eIF-2 Kinase