The mechanism of mRNA cap recognition

• 成果类型: Article
• 署名作者: Gentry, Riley C.; Ide, Nicholas A.; Comunale, Victoria M.; Hartwick, Erik W.; Kinz-Thompson, Colin D.; Gonzalez Jr, Ruben L.
• 署名单位: Columbia University; Columbia University; University of Colorado System; University of Colorado Boulder; Rutgers University System; Rutgers University Newark
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2489
• DOI: 10.1038/s41586-024-08304-0
• 发表日期: 2025-01-16
• 关键词: translation initiation; saccharomyces-cerevisiae; dependent translation; unwinding activities; helicase activity; eif4g; complex; binding; RECRUITMENT; selection

摘要

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.