Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR - PubMed (original) (raw)
. 2005 Sep 23;122(6):887-900.
doi: 10.1016/j.cell.2005.06.044.
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- PMID: 16179258
- DOI: 10.1016/j.cell.2005.06.044
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Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR
Arvin C Dar et al. Cell. 2005.
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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.
Comment in
- PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking.
Taylor SS, Haste NM, Ghosh G. Taylor SS, et al. Cell. 2005 Sep 23;122(6):823-5. doi: 10.1016/j.cell.2005.09.007. Cell. 2005. PMID: 16179248 Review.
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