Sugar phosphate activation of the stress sensor eIF2B.
Sugar phosphate activation of the stress sensor eIF2B.
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DOI：
10.1038/s41467-021-23836-z
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发表时间：
2021-06-08
影响因子：
16.6
通讯作者：
Sidrauski C
中科院分区：
文献类型：
--
作者：
Hao Q;Heo JM;Nocek BP;Hicks KG;Stoll VS;Remarcik C;Hackett S;LeBon L;Jain R;Eaton D;Rutter J;Wong YL;Sidrauski C
多亚基翻译起始因子eIF2B是蛋白质合成的控制节点。eIF2B活性通过其底物eIF2的应激响应性磷酸化进行规范调节。eIF2B调节亚复合物在进化上与糖代谢酶相关，但这种关系的生物学相关性尚不清楚。为了鉴定可能调节eIF2B的天然配体，我们进行了基于结合和活性的无偏筛选，然后进行了结构研究。我们发现糖磷酸占据了eIF2Bα亚基中的祖先催化位点，促进eIF2B全酶的形成并增强对eIF2的酶活性。导致消失性白色物质病的eIF 2B α配体口袋中的突变体无法接合并且不受磷酸糖的刺激。这些数据强调了变构代谢物调节对于适当eIF2B功能的重要性。我们认为eIF 2B进化为通过糖磷酸传感将营养状态与蛋白质合成速率结合起来，这是能量消耗最高的细胞过程之一。已知翻译起始因子eIF2B的活性通过其底物eIF2的应激响应性磷酸化来调节。在这里，作者揭示了eIF2B通过糖磷酸盐结合的调节，表明营养状态和蛋白质合成速率之间存在联系。
The multi-subunit translation initiation factor eIF2B is a control node for protein synthesis. eIF2B activity is canonically modulated through stress-responsive phosphorylation of its substrate eIF2. The eIF2B regulatory subcomplex is evolutionarily related to sugar-metabolizing enzymes, but the biological relevance of this relationship was unknown. To identify natural ligands that might regulate eIF2B, we conduct unbiased binding- and activity-based screens followed by structural studies. We find that sugar phosphates occupy the ancestral catalytic site in the eIF2Bα subunit, promote eIF2B holoenzyme formation and enhance enzymatic activity towards eIF2. A mutant in the eIF2Bα ligand pocket that causes Vanishing White Matter disease fails to engage and is not stimulated by sugar phosphates. These data underscore the importance of allosteric metabolite modulation for proper eIF2B function. We propose that eIF2B evolved to couple nutrient status via sugar phosphate sensing with the rate of protein synthesis, one of the most energetically costly cellular processes. The activity of translation initiation factor eIF2B is known to be modulated through stress-responsive phosphorylation of its substrate eIF2. Here, the authors uncover the regulation of eIF2B by the binding of sugar phosphates, suggesting a link between nutrient status and the rate of protein synthesis.
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影响因子：
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作者：
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