Structural and functional roles of the microprotein NoBody in mRNA decapping and decay

项目总结/摘要 该项目描述了一种新的人类微蛋白的发现和表征， 细胞RNA衰变。RNA降解或周转是转录后基因表达的关键机制 调节，不仅在其寿命结束时降解正常细胞RNA，而且降解疾病相关的mRNA 它们被降解以防止产生有毒的突变蛋白质。我们的新多肽，我们称之为 NoBody是“未注释的P体相关多肽”，由长的非编码RNA翻译而来。 NoBody的大小仅为7 kDa，并且本质上是无序的。尽管缺乏结构，但NoBody高度 在哺乳动物中是保守的，我们表明它特异性地与参与关键步骤的第一步的蛋白质相互作用。 RNA周转途径- mRNA脱帽-并且它与数百种细胞的丰度有关。 成绩单我们建议阐明这种微蛋白的生物化学功能和结构， mRNA脱帽蛋白，以及受其控制的基因和生物过程。的 这一建议的意义在于，我们将揭示一种全新的mRNA衰变调节机制- 一种以前未知的微蛋白对mRNA去帽的调节。更广泛地说，这项工作将 这表明，创新的，基于蛋白质组学的新基因发现平台有可能揭示 重要细胞过程和疾病中的新分子参与者。

Project Summary/Abstract This project describes the discovery and characterization of a novel human microprotein that functions in cellular RNA decay. RNA decay, or turnover, is a critical mechanism of post-transcriptional gene expression regulation, degrading not only normal cellular RNA at the end of its lifetime, but also disease-related mRNAs that are degraded to prevent production of toxic, mutant proteins. Our novel polypeptide, which we term NoBody for “non-annotated P-body associated polypeptide”, is translated from a long non-coding RNA. NoBody is only 7 kDa in size, and is intrinsically disordered. Despite its lack of structure, NoBody is highly conserved in mammals, and we show that it specifically interacts with proteins involved in the first step of a key RNA turnover pathway – mRNA decapping – and that it is linked to the abundances of hundreds of cellular transcripts. We propose to elucidate the biochemical function and structure of this microprotein in complex with mRNA decapping proteins, as well as the genes and biological processes that are under its control. The significance of this proposal is that we will reveal an entirely novel mechanism of regulation of mRNA decay – modulation of mRNA decapping by a previously unknown microprotein. More broadly, this work will demonstrate that innovative, proteomics-based platforms for new gene discovery have the potential to reveal new molecular players in important cellular processes and disease.