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

微生物蛋白 NoBody 在 mRNA 脱帽和衰变中的结构和功能作用

• 批准号: 10001040
• 负责人: Sarah Ann Slavoff
• 金额: $ 32.48万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001040
• 关键词: 7-methylguanosine; Accounting; Affect; Affinity; Binding; Biochemical; Biological Assay; Biological Process; Catalysis; Cell physiology; Cells; Complex; Disease; Elements; Enhancers; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Half-Life; Human; Human Genome; Hydrolysis; Knowledge; Label; Link; Mammals; Measures; Mediating; Messenger RNA; Metabolic; Modeling; Modernization; Molecular; Nonsense-Mediated Decay; Open Reading Frames; Orphan; Pathway interactions; Process; Production; Proteins; Proteomics; Quality Control; RNA; RNA Decay; Regulation; Reporter Genes; Reporting; Role; Specificity; Structure; Techniques; Technology; Transcript; Transcription Process; Translating; Untranslated RNA; Work; base; biophysical properties; conformational alteration; gene discovery; innovation; insight; intermolecular interaction; mRNA Decay; mRNA Transcript Degradation; mRNA decapping; mutant; novel; polypeptide; prevent; protein protein interaction; stoichiometry

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.

项目摘要/摘要 该项目描述了一种新的人类微蛋白的发现和鉴定，该蛋白具有 细胞的核糖核糖核酸会腐烂。RNA衰变或更替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的细胞RNA，而且还降解与疾病相关的mRNA 它们被降解以防止产生有毒的突变蛋白。我们的新型多肽，我们称之为 无人为“非注释的P-小体相关多肽”，是从一个长的非编码RNA翻译而来的。 没有人只有7 kDa大小，本质上是无序的。尽管它缺乏结构，但没有人高度 在哺乳动物中保守，我们证明它与关键的第一步所涉及的蛋白质特异性地相互作用 核糖核酸周转途径--信使核糖核酸分解--它与数百个细胞的丰度有关 成绩单。我们建议阐明该微蛋白的生化功能和结构的复合体 信使核糖核酸解离蛋白，以及在其控制下的基因和生物过程。这个 这一提议的意义在于，我们将揭示一种全新的调节mRNA衰变的机制-- 一种先前未知的微蛋白对信使核糖核酸解离的调节。更广泛地说，这项工作将 证明创新的、基于蛋白质组学的新基因发现平台有可能揭示 在重要的细胞过程和疾病中扮演新的分子角色。