New Mechanisms of the Pseudouridine Synthase Module in Mitoribosome Assembly

项目总结/摘要 RNA修饰物协调线粒体核糖体组装途径的重要步骤;然而，我们的研究发现， 对控制这些RNA编辑因子的信号的有限理解阻碍了我们对如何控制这些RNA编辑因子的了解。 这些重要的调节因子使复杂疾病中的线粒体蛋白质组变形。在哺乳动物中， RPUSD 4假尿苷（Y）合酶与新鉴定的辅助因子合作催化 线粒体核糖体RNA（rRNA）的假尿苷酸化。虽然必要的因素， 线粒体rRNA假尿苷化已被注释，其分子机制， Y合酶模块对组装线粒体核糖体发挥了精细的特异性， 未知此外，越来越多的证据表明，rRNA假尿苷化失调与线粒体 遗传性疾病，强调了这种未充分研究的RNA修饰调控的重要性， 网络为了解决这些缺点，我们将采用一个跨学科的计划，结合混合动力汽车， 结构生物学基因组学和生物化学。这种综合方法将解决关键问题， 在线粒体RNA加工中，包括：1）RPUSD 4 Y合酶如何发挥严格的 其单一rRNA修饰位点的特异性？2)为什么线粒体疾病突变失调 Y合酶模块3)Y合酶模块如何识别装配核糖体？ 定义协调rRNA基本过程的复杂分子信号 假尿苷化将为启动利用线粒体RNA的创新计划提供框架 线粒体疾病患者的利益的处理系统。

PROJECT SUMMARY/ABSTRACT RNA modifiers coordinate essential steps of the mitochondrial ribosome assembly pathway; yet our limited understanding of the signals controlling these RNA editing factors hinders our knowledge of how these important regulators misshape the mitochondrial proteome in complex diseases. In mammals, the RPUSD4 pseudouridine (Y) synthase collaborates with newly identified auxiliary factors to catalyze pseudouridylation of mitochondrial ribosomal RNA (rRNA). Although the factors necessary for mitochondrial rRNA pseudouridylation have been annotated, the molecular mechanisms by which the Y synthase module exerts exquisite specificity towards assembling mitochondrial ribosomes is unknown. Moreover, mounting evidence links dysregulated rRNA pseudouridylation to mitochondrial genetic disorders, underscoring the importance of this underexplored RNA modification regulatory network. To address these shortcomings, we will apply a cross-disciplinary program combining hybrid structural biology, genomics, and biochemistry. This integrative approach will address critical questions in mitochondrial RNA processing, including: 1) How does the RPUSD4 Y synthase exerts strict specificity for its single rRNA modification site? 2) Why do mitochondrial disease-mutations dysregulate the Y synthase module? 3) How does the Y synthase module recognize assembling ribosomes? Defining the intricate molecular signals coordinating the fundamental process of rRNA pseudouridylation will set a framework to launch innovative programs that exploit mitochondrial RNA processing systems for the benefit of mitochondrial disease patients.