Structural basis for the inhibition of translation through eIF2α phosphorylation

One of the responses to stress by eukaryotic cells is the down-regulation of protein synthesis by phosphorylation of translation initiation factor eIF2. Phosphorylation results in low availability of the eIF2 ternary complex (eIF2-GTP-tRNAi) by affecting the interaction of eIF2 with its GTP-GDP exchange factor eIF2B. We have determined the cryo-EM structure of yeast eIF2B in complex with phosphorylated eIF2 at an overall resolution of 4.2 angstrom. Two eIF2 molecules bind opposite sides of an eIF2B hetero-decamer through eIF2 alpha-D1, which contains the phosphorylated Ser51. eIF2 alpha-D1 is mainly inserted between the N-terminal helix bundle domains of delta and alpha subunits of eIF2B. Phosphorylation of Ser51 enhances binding to eIF2B through direct interactions of phosphate groups with residues in eIF2B alpha and indirectly by inducing contacts of eIF2 alpha helix 58-63 with eIF2B delta leading to a competition with Met-tRNA(i).