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Abstract
Protein synthesis in eukaryotes is controlled by signals and stresses via a common pathway, called the integrated stress response (ISR). Phosphorylation of the translation initiation factor eIF2 alpha at a conserved serine residue mediates translational control at the ISR core. To provide insight into the mechanism of translational control we have determined the structures of eIF2 both in phosphorylated and unphosphorylated forms bound with its nucleotide exchange factor eIF2B by electron cryomicroscopy. The structures reveal that eIF2 undergoes large rearrangements to promote binding of eIF2α to the regulatory core of eIF2B comprised of the eIF2B alpha, beta and delta subunits. Only minor differences are observed between eIF2 and eIF2αP binding to eIF2B, suggesting that the higher affinity of eIF2αP for eIF2B drives translational control. We present a model for controlled nucleotide exchange and initiator tRNA binding to the eIF2/eIF2B complex.
During the integrated stress response, translation is modulated through the phosphorylation of translation initiation factor eIF2 and the formation of a complex with eIF2B. Here the authors present structures of the eIF2:eIF2B complex with and without phosphorylation, shedding light on how eIF2 phosphorylation regulates translation.
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1 The University of Manchester, Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407)
2 The University of Manchester, Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407); Old Road Campus Research Building Roosevelt Drive, The Jenner Institute, Oxford, UK (GRID:grid.5379.8)
3 The University of Manchester, Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407); University of the Punjab, Department of Microbiology and Molecular Genetics, Lahore, Pakistan (GRID:grid.11173.35) (ISNI:0000 0001 0670 519X)