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 its interaction with its GTP-GDP exchange factor eIF2B. We have determined the cryo-EM structure of eIF2B in complex with phosphorylated eIF2 at an overall resolution of 4.15 [A]. Two eIF2 molecules bind opposite sides of an eIF2B hetero-decamer through eIF2-D1, which contains the phosphorylated Ser51. eIF2-D1 is mainly inserted between the N-terminal helix bundle domains of {delta} and subunits of eIF2B. Phosphorylation of Ser51 enhances binding to eIF2B through direct interactions of phosphate groups with residues in eIF2B and indirectly by inducing contacts of eIF2 helix 58-63 with eIF2B{delta} leading to a competition with Met-tRNAi.