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Regulation and function of bacterial 100S ribosome

细菌100S核糖体的调控和功能

基本信息

批准号：
10225376
负责人：
Mee-Ngan F Yap
金额：
$ 32.33万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-09-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225376
关键词：
Address Aging Animals Anti-Bacterial Agents Bacteria Bacterial Proteins Binding Binding Proteins Biochemical Biochemistry Biogenesis Biology Biophysics Cells Chronic Complex Cyanobacterium Data Dimerization Dissociation Distant Equilibrium Escherichia coli Firmicutes Fluorescence Polarization Functional disorder Gammaproteobacteria Genes Genetic Genetic Transcription Genus staphylococcus Goals Growth Guanosine Guanosine Triphosphate Hibernation Human Infection Kinetics Knock-out Label Lead Link Maintenance Mediating Messenger RNA Metabolism Molecular Mutagenesis Pathogenesis Phase Phenotype Physiologic pulse Physiological Probiotics Process Production Protein Biosynthesis Proteins Regulation Regulatory Pathway Relapse Resistance Ribonucleases Ribosomes Role Sigma Factor Staphylococcal Infections Staphylococcus aureus Staphylococcus aureus infection Structure System Testing Translation Initiation Translations Up-Regulation Uridine Variant analog attenuation crosslink derepression dimer exhaust genome-wide host colonization in silico in vivo insight interdisciplinary approach light scattering logarithm monomer mouse model mutant novel pathogen pathogenic bacteria prevent preventive intervention ribosome profiling

项目摘要

SUMMARY During bacterial protein synthesis, the 30S and 50S ribosomal subunits assemble into the translationally active 70S ribosome on template mRNA. In the Gram-positive human bacterial pathogen Staphylococcus aureus, a single small ribosome-binding protein called hibernation-promoting factor (HPFSa) stimulates the dimerization of 2.5-MDa 70S monomers to form the translationally silent 100S complex. The physiological function of the 100S ribosome remains enigmatic because the temporal abundance of the 100S ribosome varies considerably among different bacterial phyla, the global impact of the 100S ribosome on translation is completely unknown, and hpf null mutants of different bacteria lack a common phenotype. Moreover, distantly related gammaproteobacteria, such as E. coli, require two proteins (RMFEc and HPFEc) to achieve 100S complex formation. Recent data from our group demonstrate that HPFSa is essential for the bacterial survival and maintenance of the ribosome pool in aging S. aureus cells. Surprisingly, eliminating hpfSa causes the derepression of only a subset of genes at translational initiation. Our goal is to establish a mechanistic understanding of the function of the 100S ribosome in translational capacity and staphylococcal pathogenesis. We will take a multi-disciplinary approach that spans genetics, molecular biophysics, biochemistry, and whole animal infection studies. Aim 1 will determine the process and factors involved in the reversible conversion of 70S and 100S ribosomes. Aim 2 will determine how the HPFSa/100S ribosome inhibits translation in a gene- specific manner. Aim 3 will identify the roles of the 100S complex in ribosome turnover and staphylococcal pathophysiology. These aims have the potential to produce novel insights into ribosome metabolism and inspire alternate treatments for persistent and relapsed staphylococcal infections that are intimately linked to survive for an extended period inside the host.

总结在细菌蛋白质合成过程中，30 S和50 S核糖体亚基组装成互补的核糖体。活性70 S核糖体。在革兰氏阳性人类细菌病原体葡萄球菌中金黄色葡萄球菌，一个单一的小核糖体结合蛋白称为冬眠促进因子（HPFSa）刺激 2.5-MDa 70 S单体二聚化形成沉默的100 S复合物。生理 100 S核糖体的功能仍然是个谜，因为100 S核糖体的时间丰度在不同的细菌门之间差异很大，100 S核糖体对翻译的全球影响是完全未知，不同细菌的HPF无效突变体缺乏共同的表型。此外，远相关的γ-变形菌，如E.大肠杆菌，需要两种蛋白质（RMFEc和HPFEc）来实现100 S 复杂的形成。我们小组最近的数据表明，HPFSa是细菌生存所必需的和维持衰老S.金黄色葡萄球菌细胞令人惊讶的是，消除hpfSa会导致在翻译起始时仅对一部分基因进行去阻遏。我们的目标是建立一个理解100 S核糖体在翻译能力和葡萄球菌发病机制中的功能。我们将采取多学科的方法，跨越遗传学，分子生物物理学，生物化学和整体动物感染研究。目标1将确定可逆转化的过程和影响因素， 70 S和100 S核糖体。目标2将确定HPFSa/100 S核糖体如何抑制基因翻译- 具体方式。目的3将确定100 S复合物在核糖体转换和葡萄球菌中的作用病理生理学这些目标有可能对核糖体代谢产生新的见解，启发了持续性和复发性葡萄球菌感染的替代治疗，在宿主体内存活很长时间。