The structural basis of translational control by eIF2 phosphorylation

Tomas Adomavicius, Margherita Guaita, Yu Zhou, Martin D. Jennings, Zakia Latif, Alan M. Roseman () and Graham D. Pavitt ()
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Tomas Adomavicius: The University of Manchester
Margherita Guaita: The University of Manchester
Yu Zhou: The University of Manchester
Martin D. Jennings: The University of Manchester
Zakia Latif: The University of Manchester
Alan M. Roseman: The University of Manchester
Graham D. Pavitt: The University of Manchester

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10167-3

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