Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.
Mol Cell. 2016 Nov 3;64(3):467-479. doi: 10.1016/j.molcel.2016.09.020. Epub 2016 Oct 20.
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 (4E-BPs). 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.
真核起始因子 4G（eIF4G）通过与帽结合蛋白 eIF4E 的相互作用，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，并且自然受到 4E 结合蛋白（4E-BPs）的调节。4E-BPs 和 eIF4G 通过共享的经典 4E 结合基序与 eIF4E 背侧表面竞争结合，但也包含辅助 eIF4E 结合序列，这些序列假定与 eIF4E 非重叠表面接触。然而，真核生物 eIF4G 辅助序列如何与 eIF4E 结合尚不清楚。在这里，我们描述了人源和黑腹果蝇 eIF4E-eIF4G 复合物的晶体结构，这些结构出人意料地揭示了 eIF4G 辅助序列通过与 4E-BPs 相似的模式结合到 eIF4E 的侧表面。我们的研究提供了 eIF4E-eIF4G 复合物的分子模型，阐明了 4E-BPs 的竞争机制，并能够合理设计选择性 eIF4G 抑制剂来抑制疾病中失调的翻译。
