Marintchev Assen
Department of Pharmacology, Physiology, & Biophysics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, U.S.A.
Biochem Soc Trans. 2025 Jun 30;53(3):593-602. doi: 10.1042/BST20253022.
Eukaryotic translation initiation typically involves recruitment of the 43S ribosomal pre-initiation complex (PIC) to the 5'-end of the mRNA to form the 48S PIC, followed by scanning in search of a start codon in a favorable nucleotide complex. The start codon is recognized through base-pairing with the anticodon of the initiator Met-tRNAi. The stringency of start codon selection controls the probability of initiation from a start codon in a suboptimal nucleotide context. Met-tRNAi itself is recruited to the 43S PIC by the eukaryotic translation initiation factor 2 (eIF2), in the form of the eIF2-GTP•Met-tRNAi ternary complex (TC). GTP hydrolysis by eIF2, promoted by its GTPase-activating protein eIF5, leads to the release of eIF2-GDP from the PIC. Recycling of eIF2-GDP to TC is promoted by the guanine nucleotide exchange factor eIF2B. Its inhibition by a number of stress factors triggers the integrated stress response (ISR). This review describes the recent advances in elucidating the interactions of eIF2 and its partners, with an emphasis on the timing and dynamics of their binding to, and release from the PIC. Special attention is given to the regulation of the stringency of start codon selection and the ISR. The discussion is mostly limited to translation initiation in mammals and budding yeast.
真核生物的翻译起始通常涉及将43S核糖体预起始复合物（PIC）募集到mRNA的5'端以形成48S PIC，随后进行扫描以在合适的核苷酸复合物中寻找起始密码子。起始密码子通过与起始甲硫氨酰 - tRNAi的反密码子碱基配对来识别。起始密码子选择的严格性控制了在次优核苷酸环境中从起始密码子起始翻译的概率。甲硫氨酰 - tRNAi本身以真核生物翻译起始因子2（eIF2）的eIF2 - GTP•甲硫氨酰 - tRNAi三元复合物（TC）的形式被募集到43S PIC。由其GTP酶激活蛋白eIF5促进的eIF2的GTP水解导致eIF2 - GDP从PIC释放。鸟嘌呤核苷酸交换因子eIF2B促进eIF2 - GDP循环再生成TC。其受到多种应激因素的抑制会触发综合应激反应（ISR）。本综述描述了在阐明eIF2及其伙伴相互作用方面的最新进展，重点关注它们与PIC结合和从PIC释放的时间和动力学。特别关注起始密码子选择严格性的调节和ISR。讨论主要限于哺乳动物和芽殖酵母中的翻译起始。
