The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation
The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation
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DOI：
10.1016/j.molcel.2016.09.020
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发表时间：
2016-11-03
期刊：
影响因子：
16
通讯作者：
Izaurralde, Elisa
中科院分区：
文献类型：
--
作者：
Gruener, Stefan;Peter, Daniel;Izaurralde, Elisa
真核起始因子 4G (eIF4G) 通过与帽结合蛋白 eIF4E 相互作用，在翻译起始中发挥核心作用。这种相互作用是抑制翻译的主要药物靶点，并且自然地受到 4E 结合蛋白 (4EBP) 的调节。 4E-BP 和 eIF4G 通过共享的规范 4E 结合基序竞争与 eIF4E 背表面的结合，但也包含辅助 eIF4E 结合序列，假定这些序列接触非重叠的 eIF4E 表面。然而，后生动物 eIF4G 辅助序列如何结合 eIF4E 尚不清楚。在这里，我们描述了人和果蝇 eIF4E-eIF4G 复合物的晶体结构，意外地揭示了 eIF4G 辅助序列使用与 4E-BP 类似的模式结合到 eIF4E 的侧面。我们的研究提供了 eIF4E-eIF4G 复合物的分子模型，阐明了 4E-BP 的竞争机制，并能够合理设计选择性 eIF4G 抑制剂，以抑制疾病中的翻译失调。
Eukaryotic initiation factor 4G (eIF4G) plays a central role in translation initiation through its interactions with the cap-binding protein eIF4E. This interaction is a major drug target for repressing translation and is naturally regulated by 4E-binding proteins (4EBPs). 4E-BPs and eIF4G compete for binding to the eIF4E dorsal surface via a shared canonical 4E-binding motif, but also contain auxiliary eIF4E-binding sequences, which were assumed to contact non-overlapping eIF4E surfaces. However, it is unknown how metazoan eIF4G auxiliary sequences bind eIF4E. Here, we describe crystal structures of human and Drosophila melanogaster eIF4E-eIF4G complexes, which unexpectedly reveal that the eIF4G auxiliary sequences bind to the lateral surface of eIF4E, using a similar mode to that of 4E-BPs. Our studies provide a molecular model of the eIF4E-eIF4G complex, shed light on the competition mechanism of 4E-BPs, and enable the rational design of selective eIF4G inhibitors to dampen dysregulated translation in disease.