Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor of the GTPase eIF2, which brings the initiator Met-tRNA_i to the ribosome in the form of the eIF2-GTP·Met-tRNA_i ternary complex (TC). The activity of eIF2B is inhibited by phosphorylation of its substrate eIF2 by several stress-induced kinases, which triggers the integrated stress response (ISR). The ISR plays a central role in maintaining homeostasis in the cell under various stress conditions, and its dysregulation is a causative factor in the pathology of a number of neurodegenerative disorders. Over the past three decades, virtually every aspect of eIF2B function has been the subject of uncertainty or controversy: from the catalytic mechanism of nucleotide exchange, to whether eIF2B only catalyzes nucleotide exchange on eIF2 or also promotes binding of Met-tRNA_i to eIF2-GTP to form the TC. Here, we provide the first complete thermodynamic analysis of the process of recycling of eIF2-GDP to the TC. The available evidence leads to the conclusion that eIF2 is channeled from the ribosome (as an eIF5·eIF2-GDP complex) to eIF2B, converted by eIF2B to the TC, which is then channeled back to eIF5 and the ribosome. The system has evolved to be regulated by multiple factors, including post-translational modifications of eIF2, eIF2B, and eIF5, as well as directly by the energy balance in the cell, through the GTP:GDP ratio.

中文翻译：

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eIF2B的作用和调节机制：热力学观点

真核翻译起始因子2B（eIF2B）是GTPase eIF2的鸟嘌呤核苷酸交换因子，它将起始子Met-tRNA _i以eIF2-GTP·Met-tRNA _i的形式带入核糖体。三元复合物（TC）。eIF2B的活性受到几种应激诱导的激酶对其底物eIF2磷酸化的抑制，从而触发了整合应激反应（ISR）。在各种压力条件下，ISR在维持细胞内稳态方面起着核心作用，其失调是许多神经退行性疾病病理学的致病因素。在过去的三个十年中，eIF2B功能的各个方面已经无法保证或存在争议的问题：从核苷酸交换的催化机制，eIF2B是否仅催化上的eIF2核苷酸交换或还促进的Met-tRNA的结合_我到eIF2-GTP以形成TC。在这里，我们提供了eIF2-GDP向TC回收过程的第一个完整的热力学分析。现有证据可得出以下结论：eIF2从核糖体（作为eIF5·eIF2-GDP复合体）传导至eIF2B，再由eIF2B转化为TC，然后再传导回eIF5和核糖体。该系统已发展为受多种因素调节，包括eIF2，eIF2B和eIF5的翻译后修饰，以及通过GTP：GDP比率直接受细胞内能量平衡的调节。