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Structural and functional basis for protein-based eukaryotic RNA processing

基于蛋白质的真核RNA加工的结构和功能基础

基本信息

批准号：
9529976
负责人：
Markos Koutmos
金额：
$ 9.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9529976
关键词：
Active Sites Algae Amino Acids Binding Biochemical Biochemistry Biological Biological Assay Biological Models Biophysics Catalytic Domain Catalytic RNA Cell Nucleus Cells Chemistry Chloroplasts Cleaved cell Code Complex Crystallization Data Development Disease Drosophila Proteins Drosophila genus Drosophila melanogaster Proteins Enzymes Essential Hypertension Etiology Eukaryota Gene Mutation Genes Genome Goals Health Human In Vitro Individual Inherited Investigation Kinetics Lead Life Link MELAS Syndrome Measures Messenger RNA Mitochondria Mitochondrial Diseases Mitochondrial Myopathies Modification Molecular Mutation Nuclear Organelles Pancreatic ribonuclease Physiological Plants Protein Biosynthesis Protein Overexpression Proteins RNA RNA Processing RNA methylation RNase P Reaction Regulation Reporting Research Ribosomal RNA Ribosomes Roentgen Rays Role Structure Techniques Testing Thermodynamics Transcript Transfer RNA Work X-Ray Crystallography base catalyst fly in vivo in vivo Model mutant novel overexpression public health relevance structural biology

项目摘要

DESCRIPTION (provided by applicant): Transfer RNAs (tRNAs) are essential biological adaptor molecules connecting mRNA to protein synthesis. Given their important biological role, correct maturation and modification of tRNAs is strictly required for cell health and viability. Ths is particularly salient in mitochondria, where mitochondrial tRNA gene mutations are the prevalent cause of mitochondrial disease. In organellar genomes, tRNAs "punctuate" rRNA and protein coding genes, making 5' end processing of tRNA transcripts essential not only for tRNA maturation, but also for the 3' end processing of the preceding sequences. Across all domains of life, tRNA 5' end maturation is catalyzed by the essential enzyme ribonuclease P (RNase P). Until recently all known RNase P enzymes were thought to include a catalytic RNA component. However, the discovery of Protein Only RNase P (PRORP) in human mitochondria and A. thaliana chloroplasts, mitochondria, and nuclei has shifted this paradigm. Correct tRNA maturation by PRORP is essential for human health; mutations in PRORP and its substrates that disrupt tRNA 5' end processing are linked to diseases including maternally inherited essential hypertension, mitochondrial myopathy, MELAS, and HSD10- disease. Our work will use biophysical, biochemical and cell- biological techniques to determine the structure and mechanism of PRORPs, as well as develop an in vivo model system for assessing the physiological role of PRORPs. These studies will establish a framework for understanding the molecular basis of, and ultimately treating, a range of mitochondrial diseases. Together, our highly interdisciplinary work will provide the first structural and mechanistic information on mitochondrial tRNA 5' end processing in higher eukaryotes.

描述（由申请人提供）：转移 RNA (tRNA) 是将 mRNA 连接到蛋白质合成的重要生物接头分子。鉴于其重要的生物学作用，tRNA 的正确成熟和修饰对于细胞健康和活力是严格要求的。这在线粒体中尤为突出，线粒体 tRNA 基因突变是线粒体疾病的普遍原因。在细胞器基因组中，tRNA“打断”rRNA 和蛋白质编码基因，使得 tRNA 转录物的 5' 末端加工不仅对于 tRNA 成熟至关重要，而且对于前面序列的 3' 末端加工也至关重要。在生命的所有领域，tRNA 5' 末端成熟均由必需酶核糖核酸酶 P (RNase P) 催化。直到最近，所有已知的 RNase P 酶都被认为包含催化 RNA 成分。然而，在人类线粒体和拟南芥叶绿体、线粒体和细胞核中发现纯蛋白质 RNase P (PRORP) 改变了这一范式。 PRORP 正确的 tRNA 成熟对于人类健康至关重要； PRORP 及其底物中破坏 tRNA 5' 末端加工的突变与母系遗传性原发性高血压、线粒体肌病、MELAS 和 HSD10 疾病等疾病有关。我们的工作将利用生物物理、生物化学和细胞生物学技术来确定 PRORP 的结构和机制，并开发一个体内模型系统来评估 PRORP 的生理作用。这些研究将为理解一系列线粒体疾病的分子基础并最终治疗一系列线粒体疾病建立一个框架。总之，我们高度跨学科的工作将提供有关高等真核生物中线粒体 tRNA 5' 末端加工的第一个结构和机制信息。