eIF2B and the Integrated Stress Response: A Structural and Mechanistic View
eIF2B and the Integrated Stress Response: A Structural and Mechanistic View
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DOI：
10.1021/acs.biochem.0c00132
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发表时间：
2020-04-07
期刊：
影响因子：
2.9
通讯作者：
Ito, Takuhiro
中科院分区：
文献类型：
--
作者：
Marintchev, Assen;Ito, Takuhiro
真核翻译起始因子 eIF2 是一种 GTP 酶，它将起始子 Met-tRNA(i) 带到核糖体，作为 eIF2-GTP 中心点 Met-tRNA(i) 三元复合物 (TC)。 TC 再生由鸟嘌呤核苷酸交换因子 (GEF) eIF2B 催化。 eIF2 被几种应激诱导的激酶磷酸化，将其转化为 eIF2B 的竞争性抑制剂。抑制 eIF2B 活性会降低细胞 TC 浓度，进而触发综合应激反应 (ISR)。根据其激活程度和持续时间，ISR 可以保护细胞免受应激，或者本身可以诱导细胞凋亡。 ISR 失调是多种神经退行性疾病病理学的致病因素，而 ISR 抑制剂具有神经保护作用。 eIF2B 是一个有前途的治疗靶点，这一认识引发了人们对其结构及其作用和调节机制的极大兴趣。最近，四个小组发表了 eIF2B 及其底物 eIF2 和/或其抑制剂磷酸化 eIF2 [eIF2(alpha-P)] 的冷冻电子显微镜结构。虽然非生产性 eIF2B 中心点 eIF2(alpha-P) 复合物的所有三种结构彼此相似，但生产性 eIF2B 中心点 eIF2 复合物的已发表结构之间存在明显分歧。一组报告了与非生产性复合体相似的结构，而另外两组观察到了截然不同的 eIF2B 中心点 eIF2 复合体。在此，我们讨论最近关于eIF2B的结构、功能和调控的报道；使用 ISR 抑制剂治疗神经退行性疾病的临床前数据；以及新的结构和生化信息如何告知和影响 eIF2B 作为治疗靶点的使用。
The eukaryotic translation initiation factor eIF2 is a GTPase, which brings the initiator Met-tRNA(i) to the ribosome as the eIF2-GTP center dot Met-tRNA(i) ternary complex (TC). TC regeneration is catalyzed by the guanine nucleotide exchange factor (GEF) eIF2B. eIF2 phosphorylation by several stress-induced kinases converts it into a competitive inhibitor of eIF2B. Inhibition of eIF2B activity lowers cellular TC concentrations, which in turn triggers the integrated stress response (ISR). Depending on its degree of activation and duration, the ISR protects the cell from the stress or can itself induce apoptosis. ISR dysregulation is a causative factor in the pathology of multiple neurodegenerative disorders, while ISR inhibitors are neuroprotective. The realization that eIF2B is a promising therapeutic target has triggered significant interest in its structure and its mechanisms of action and regulation. Recently, four groups published the cryo-electron microscopy structures of eIF2B with its substrate eIF2 and/or its inhibitor, phosphorylated eIF2 [eIF2(alpha-P)]. While all three structures of the nonproductive eIF2B center dot eIF2(alpha-P) complex are similar to each other, there is a sharp disagreement between the published structures of the productive eIF2B center dot eIF2 complex. One group reports a structure similar to that of the nonproductive complex, whereas two others observe a vastly different eIF2B center dot eIF2 complex. Here, we discuss the recent reports on the structure, function, and regulation of eIF2B; the preclinical data on the use of ISR inhibitors for the treatment of neurodegenerative disorders; and how the new structural and biochemical information can inform and influence the use of eIF2B as a therapeutic target.