美国哥伦比亚大学Ruben L. Gonzalez Jr团队近期取得重要工作进展。他们研究揭示了mRNA帽识别的机制。相关研究成果2024年12月11日在线发表于《自然》杂志上。

据介绍，在翻译启动过程中，mRNA分子必须被识别和激活，以便装载到核糖体中。在这个限速步骤中，异三聚体蛋白真核起始因子eIF4F必须识别并有效地与mRNA 5'端的7-甲基鸟苷帽相互作用，随后激活该mRNA。尽管其在基因表达中起着基础性的调节作用，但帽识别和mRNA激活背后的分子事件尚不清楚。

研究人员开发了一个单分子荧光成像系统，以检查eIF4F在全长天然mRNA分子上区分生产和非生产位置的动力学。在单分子水平上，研究人员观察到eIF4F沿mRNA长度的随机采样，并确定eIF4F亚基之间的变构通信，最终驱动帽识别和随后的mRNA激活。

这一研究揭示了eIF4F每个亚基的功能，研究人员通过提出一个mRNA激活模型得出结论，该模型精确地定义了激活信息的组成。该模型为理解mRNA分子如何相互区分，以及其他RNA结合蛋白如何控制翻译启动的效率提供了一个总体框架。

附：英文原文

Title: The mechanism of mRNA cap recognition

Author: Gentry, Riley C., Ide, Nicholas A., Comunale, Victoria M., Hartwick, Erik W., Kinz-Thompson, Colin D., Gonzalez, Ruben L.

Issue&Volume: 2024-12-11

Abstract: During translation initiation, mRNA molecules must be identified and activated for loading into a ribosome1,2,3. In this rate-limiting step, the heterotrimeric protein eukaryotic initiation factor eIF4F must recognize and productively interact with the 7-methylguanosine cap at the 5′ end of the mRNA and subsequently activate the message1,2,3. Despite its fundamental, regulatory role in gene expression, the molecular events underlying cap recognition and mRNA activation remain unclear3. Here we generate a single-molecule fluorescence imaging system to examine the dynamics with which eIF4F discriminates productive and non-productive locations on full-length, native mRNA molecules. At the single-molecule level, we observe stochastic sampling of eIF4F along the length of the mRNA and identify allosteric communication between the eIF4F subunits that ultimately drive cap-recognition and subsequent activation of the message. Our experiments uncover functions for each subunit of eIF4F and we conclude by presenting a model for mRNA activation that precisely defines the composition of the activated message. This model provides a general framework for understanding how mRNA molecules may be discriminated from one another and how other RNA-binding proteins may control the efficiency of translation initiation.

DOI: 10.1038/s41586-024-08304-0

Source: https://www.nature.com/articles/s41586-024-08304-0