eIF2B Mechanisms of Action and Regulation: A Thermodynamic View.
eIF2B Mechanisms of Action and Regulation: A Thermodynamic View.
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DOI：
10.1021/acs.biochem.7b00957
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发表时间：
2018-03-06
期刊：
影响因子：
2.9
通讯作者：
Marintchev A
中科院分区：
文献类型：
--
作者：
Bogorad AM;Lin KY;Marintchev A
真核生物翻译起始因子2B(EIF2B)是GTP酶eIF2的鸟核苷酸交换因子，它将启动子Met-tRNAi以eIF2-GTP·Met-tRNAi三元复合体(TC)的形式引入核糖体。EIF2B的活性被其底物eIF2的磷酸化抑制，这是由几个应激诱导的激酶触发的，从而触发了整合应激反应(ISR)。在不同的应激条件下，ISR在维持细胞内的动态平衡方面起着核心作用，它的失调是许多神经退行性疾病的致病因素。在过去的三十年里，eIF2B功能的几乎每一个方面都一直是不确定或有争议的主题：从核苷酸交换的催化机制，到eIF2B是否只催化eIF2上的核苷酸交换，或者也促进Met-tRNAi与eIF2-GTP的结合形成TC。在这里，我们向TC提供了第一个完整的eIF2-GDP回收过程的热力学分析。现有证据表明，eIF2从核糖体(以eIF5·eIF2-GDP复合体的形式)导入eIF2B，eIF2B将eIF2B转化为TC，TC再导入eIF5和核糖体。该系统已进化为受多种因素的调节，包括eIF2、eIF2B和eIF5的翻译后修饰，以及通过GTP/GDP比率直接受到细胞内能量平衡的调节。
Eukaryotic translation initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor of the GTPase eIF2, which brings the initiator Met-tRNAi to the ribosome in the form of the eIF2-GTP·Met-tRNAi 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-tRNAi 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.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1016/0006-291x(91)92109-w
发表时间：
1991-12-31
影响因子：
3.1
作者：
GROSS, M;RUBINO, MS;HESSEFORT, SM
通讯作者：
HESSEFORT, SM
影响因子：
2.9
作者：
Gromadski, KB;Wieden, HJ;Rodnina, MV
通讯作者：
Rodnina, MV
影响因子：
11.4
作者：
Gomez, E;Mohammad, SS;Pavitt, GD
通讯作者：
Pavitt, GD
DOI：
10.1111/j.1432-1033.1986.tb10490.x
发表时间：
1986-12-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
CRECHET, JB;PARMEGGIANI, A
通讯作者：
PARMEGGIANI, A