MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Instituto de Biomedicina de Valencia del Consejo Superior de Investigaciones Científicas and CIBERER-ISCIII, Valencia, 46010, Spain.
Nat Commun. 2019 Jun 14;10(1):2640. doi: 10.1038/s41467-019-10606-1.
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 Å. Two eIF2 molecules bind opposite sides of an eIF2B hetero-decamer through eIF2α-D1, which contains the phosphorylated Ser51. eIF2α-D1 is mainly inserted between the N-terminal helix bundle domains of δ and α subunits of eIF2B. Phosphorylation of Ser51 enhances binding to eIF2B through direct interactions of phosphate groups with residues in eIF2Bα and indirectly by inducing contacts of eIF2α helix 58-63 with eIF2Bδ leading to a competition with Met-tRNA.
真核细胞应对压力的反应之一是通过磷酸化翻译起始因子 eIF2 来下调蛋白质合成。磷酸化通过影响 eIF2 与其 GTP-GDP 交换因子 eIF2B 的相互作用，导致 eIF2 三元复合物 (eIF2-GTP-tRNAi) 的可用性降低。我们已经确定了酵母 eIF2B 与磷酸化 eIF2 复合物的低温电镜结构，整体分辨率为 4.2Å。两个 eIF2 分子通过 eIF2α-D1 结合 eIF2B 异源十聚体的相对两侧，eIF2α-D1 包含磷酸化的 Ser51。eIF2α-D1 主要插入 eIF2Bδ 和 α 亚基的 N 端螺旋束结构域之间。Ser51 的磷酸化通过磷酸基团与 eIF2Bα 中的残基的直接相互作用以及通过诱导 eIF2α 螺旋 58-63 与 eIF2Bδ 的接触来增强与 eIF2B 的结合，从而导致与 Met-tRNA 的竞争。
