Higher-order substrate recognition of eIF2α by the RNA-dependent protein kinase PKR

Arvin C. Dar, Thomas E. Dever, Frank Sicheri

Research output: Contribution to journalArticlepeer-review

286 Scopus citations

Abstract

In response to binding viral double-stranded RNA byproducts within a cell, the RNA-dependent protein kinase PKR phosphorylates the α 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 eIF2α. The structures reveal that eIF2α 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 eIF2α, 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 eIF2α protein kinases are discussed.

Original languageEnglish
Pages (from-to)887-900
Number of pages14
JournalCell
Volume122
Issue number6
DOIs
StatePublished - 23 Sep 2005
Externally publishedYes

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