タンパク質の運動に関する新知見が医薬品開発に大きな示唆を与える(A New Finding About Protein Motions Has Big Implications for Drug Development)

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2024-12-16 コロンビア大学

コロンビア大学のルーベン・ゴンザレス教授の研究チームは、単一分子光学顕微鏡を用いて、生体分子の動きをリアルタイムで観察する技術を開発しています。最新の研究では、タンパク質合成の初期段階で重要な役割を果たす「eIF4F」というタンパク質複合体が、メッセンジャーRNA(mRNA)のキャップ構造に直接結合するのではなく、mRNA上を「ホッピング」しながらキャップを探索することを発見しました。この知見は、がん細胞の増殖を抑制する新たな治療法の開発に寄与する可能性があります。

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mRNAキャップ認識のメカニズム The mechanism of mRNA cap recognition

Riley C. Gentry,Nicholas A. Ide,Victoria M. Comunale,Erik W. Hartwick,Colin D. Kinz-Thompson &Ruben L. Gonzalez Jr
Nature  Published:11 December 2024
DOI:https://doi.org/10.1038/s41586-024-08304-0

タンパク質の運動に関する新知見が医薬品開発に大きな示唆を与える(A New Finding About Protein Motions Has Big Implications for Drug Development)

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.

有機化学・薬学
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