Control of the eIF4E activity: structural insights and pharmacological implications.
Control of the eIF4E activity: structural insights and pharmacological implications.
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DOI：
10.1007/s00018-021-03938-z
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Di Marino D
中科院分区：
文献类型：
--
作者：
Romagnoli A;D'Agostino M;Ardiccioni C;Maracci C;Motta S;La Teana A;Di Marino D
真核生物翻译起始因子4 E（eIF 4 E）在控制mRNA翻译中的核心作用在过去的几十年中已经得到了明确的评估。eIF 4 E功能对于许多生理过程是必不可少的，例如蛋白质合成、细胞生长和分化;其活性的失调与衰老、癌症发作和进展以及神经发育障碍（例如自闭症谱系障碍（ASD）和脆性X综合征（FXS））有关。eIF 4 E和真核起始因子4G（eIF 4G）之间的相互作用对于翻译机器的组装（mRNA翻译的初始步骤）是至关重要的。一组充分表征的蛋白质，称为4 E结合蛋白（4 E-BP），通过竞争eIF 4 E表面上的相同结合位点来抑制eIF 4 E-eIF 4G相互作用。4 E-BP和eIF 4G共享一个与eIF 4 E的保守疏水补丁相互作用的典型基序。然而，最近检测到eIF 4G和几种4 E-BP的第二个非典型且不保守的结合基序。在这里，我们回顾了eIF 4 E及其分子伴侣eIF 4G和4 E-BPs之间相互作用的结构特征，重点关注最近的结构和生化证据对开发新的治疗策略的影响。抑制翻译的新型eIF 4 E靶向分子的设计可能为治疗几种疾病提供新的途径。
The central role of eukaryotic translation initiation factor 4E (eIF4E) in controlling mRNA translation has been clearly assessed in the last decades. eIF4E function is essential for numerous physiological processes, such as protein synthesis, cellular growth and differentiation; dysregulation of its activity has been linked to ageing, cancer onset and progression and neurodevelopmental disorders, such as autism spectrum disorder (ASD) and Fragile X Syndrome (FXS). The interaction between eIF4E and the eukaryotic initiation factor 4G (eIF4G) is crucial for the assembly of the translational machinery, the initial step of mRNA translation. A well-characterized group of proteins, named 4E-binding proteins (4E-BPs), inhibits the eIF4E–eIF4G interaction by competing for the same binding site on the eIF4E surface. 4E-BPs and eIF4G share a single canonical motif for the interaction with a conserved hydrophobic patch of eIF4E. However, a second non-canonical and not conserved binding motif was recently detected for eIF4G and several 4E-BPs. Here, we review the structural features of the interaction between eIF4E and its molecular partners eIF4G and 4E-BPs, focusing on the implications of the recent structural and biochemical evidence for the development of new therapeutic strategies. The design of novel eIF4E-targeting molecules that inhibit translation might provide new avenues for the treatment of several conditions.
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