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eIF2B and the Integrated Stress Response: A Structural and Mechanistic View.
Biochemistry ( IF 2.9 ) Pub Date : 2020-03-26 , DOI: 10.1021/acs.biochem.0c00132 Assen Marintchev 1 , Takuhiro Ito 2
Biochemistry ( IF 2.9 ) Pub Date : 2020-03-26 , DOI: 10.1021/acs.biochem.0c00132 Assen Marintchev 1 , Takuhiro Ito 2
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The eukaryotic translation initiation factor eIF2 is a GTPase, which brings the initiator Met-tRNAi to the ribosome as the eIF2-GTP·Met-tRNAi 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(α-P)]. While all three structures of the nonproductive eIF2B·eIF2(α-P) complex are similar to each other, there is a sharp disagreement between the published structures of the productive eIF2B·eIF2 complex. One group reports a structure similar to that of the nonproductive complex, whereas two others observe a vastly different eIF2B·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.
中文翻译：
eIF2B和综合应力响应：结构和力学观点。
真核翻译起始因子eIF2是一种GTPase，它将启动子Met-tRNAi作为eIF2-GTP·Met-tRNAi三元复合物（TC）带入核糖体。鸟嘌呤核苷酸交换因子（GEF）eIF2B催化TC再生。几种应激诱导的激酶使eIF2磷酸化，将其转化为eIF2B的竞争性抑制剂。抑制eIF2B活性可降低细胞TC浓度，进而触发整合应激反应（ISR）。根据其活化程度和持续时间，ISR可以保护细胞免受压力或自身可以诱导细胞凋亡。ISR失调是多种神经退行性疾病病理的病因，而ISR抑制剂具有神经保护作用。eIF2B是一种有前途的治疗靶点的认识引起了人们对其结构以及其作用和调节机制的极大兴趣。最近，四个小组发表了eIF2B的低温电子显微镜结构及其底物eIF2和/或其抑制剂，磷酸化的eIF2 [eIF2（α-P）]。虽然非生产性eIF2B·eIF2（α-P）配合物的所有三个结构都相似，但已公布的生产性eIF2B·eIF2配合物的结构之间存在明显分歧。一组报告的结构与非生产性复合物相似，而另两组报告的eIF2B·eIF2复合物却相差很大。在这里，我们讨论有关eIF2B的结构，功能和调控的最新报道；使用ISR抑制剂治疗神经退行性疾病的临床前数据；
更新日期：2020-03-27
中文翻译：
eIF2B和综合应力响应：结构和力学观点。
真核翻译起始因子eIF2是一种GTPase，它将启动子Met-tRNAi作为eIF2-GTP·Met-tRNAi三元复合物（TC）带入核糖体。鸟嘌呤核苷酸交换因子（GEF）eIF2B催化TC再生。几种应激诱导的激酶使eIF2磷酸化，将其转化为eIF2B的竞争性抑制剂。抑制eIF2B活性可降低细胞TC浓度，进而触发整合应激反应（ISR）。根据其活化程度和持续时间，ISR可以保护细胞免受压力或自身可以诱导细胞凋亡。ISR失调是多种神经退行性疾病病理的病因，而ISR抑制剂具有神经保护作用。eIF2B是一种有前途的治疗靶点的认识引起了人们对其结构以及其作用和调节机制的极大兴趣。最近，四个小组发表了eIF2B的低温电子显微镜结构及其底物eIF2和/或其抑制剂，磷酸化的eIF2 [eIF2（α-P）]。虽然非生产性eIF2B·eIF2（α-P）配合物的所有三个结构都相似，但已公布的生产性eIF2B·eIF2配合物的结构之间存在明显分歧。一组报告的结构与非生产性复合物相似，而另两组报告的eIF2B·eIF2复合物却相差很大。在这里，我们讨论有关eIF2B的结构，功能和调控的最新报道；使用ISR抑制剂治疗神经退行性疾病的临床前数据；
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