Physiological impact of reduced fidelity in protein synthesis

蛋白质合成保真度降低的生理影响

• 批准号: 8932246
• 负责人: JIQIANG LING
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932246
• 关键词: Affect; Amino Acyl Transfer RNA; Amino Acyl-tRNA Synthetases; Aminoglycoside Antibiotics; Antibiotics; Anticodon; Attenuated; Bacteria; Bacteria sigma factor KatF protein; Biochemical; Biochemistry; Biophysics; Cells; Codon Nucleotides; DNA; Defect; Development; Escherichia coli; Escherichia coli Proteins; Excision; Exhibits; Future; Genes; Genetic; Goals; Growth; Heat Stress Disorders; Heat-Shock Response; Heating; Host Defense; Hydrogen Peroxide; Hypochlorite; Knowledge; Laboratories; Life; Mammals; Modeling; Molecular; Multi-Drug Resistance; Mutation; Nature; Nerve Degeneration; Nutrient; Organism; Oxidants; Oxidative Stress; Pathway interactions; Peptide Hydrolases; Peptides; Peroxides; Physiological; Play; Process; Protein Biosynthesis; Proteins; Proteome; Proteomics; Quality Control; RNA Sequence Analysis; RNA Sequences; RNA, Transfer, Amino Acid-Specific; Ribosomes; Role; Site; Small RNA; Source; Staging; Starvation; Stress; Testing; Threonine-tRNA Ligase; Translational Regulation; Translations; Virus Diseases; Work; Yeasts; antimicrobial; antioxidant enzyme; base; biological adaptation to stress; cell growth regulation; drug resistant bacteria; fitness; genetic analysis; genetic information; improved; mitochondrial dysfunction; next generation; novel; oxidation; protein aggregation; public health relevance; structural biology; tool; transcriptome sequencing

 DESCRIPTION (provided by applicant): Protein synthesis is a fundamental and essential process in all three domains of life. In the past decades, advances in biochemistry, biophysics, and structural biology have improved our knowledge on the molecular mechanisms of aminoacyl-tRNA (aa-tRNA) synthesis, translational quality control, peptide elongation, and ribosomal decoding. However, we are still at a very early stage of understanding how protein synthesis is regulated in living cells and how translational regulation affects the fitness of different organisms. Protein mistranslation (an increased level of translational errors) has been shown to cause growth defects in bacteria, mitochondrial dysfunction in yeast, and neurodegeneration in mammals. It is therefore commonly accepted that mistranslation is harmful to cells and needs to be avoided. Surprisingly, we and others have shown that mistranslation is increased during oxidative stress and viral infection, leading to a recent proposal that mistranslation may play adaptive roles under certain stress conditions. Experimental evidence to support this model is currently limited, and little is known about these adaptive mechanisms at the molecular level. The objective here is to define how bacteria respond to mistranslation. Specifically, we will (a) determine the mechanism by which mistranslation adapts E. coli to peroxide stress; (b) determine the impact of mistranslation on protein aggregation in E. coli; and (c) define the role of mistranslation caused by oxidative stres in E. coli. Such work will reveal previously unknown adaptive mechanisms by which bacteria survive severe stresses, and improve the knowledge of a new class of translational regulation that enhances phenotypic diversity and fitness through fine-tuning fidelity of protein synthesis.

 描述（由申请人提供）：蛋白质合成是生命所有三个领域的基本且重要的过程。在过去，生物化学、生物物理学和结构生物学的数十年进步提高了我们对氨酰基-tRNA（aa）分子机制的了解。 -tRNA）合成、翻译质量控制、肽延伸和核糖体解码然而，我们仍处于了解活细胞中蛋白质合成如何调节以及翻译调节如何的早期阶段。蛋白质错误翻译（翻译错误水平增加）已被证明会导致细菌生长缺陷、酵母线粒体功能障碍和哺乳动物神经变性，因此人们普遍认为错误翻译对细胞和需求有害。令人惊讶的是，我们和其他人已经证明，在氧化应激和病毒感染期间，错误翻译会增加，导致最近提出错误翻译可能在某些应激条件下发挥适应性作用的观点，目前支持该模型的实验证据有限，我们对这些分子水平的适应性机制知之甚少，具体来说，我们将（a）确定错误翻译使大肠杆菌适应过氧化物应激的机制；错误翻译对大肠杆菌中蛋白质聚集的影响；以及（c）定义了大肠杆菌中氧化应激引起的错误翻译的作用，这些工​​作将揭示细菌在严重应激下生存的先前未知的适应机制，并改善细菌的生存能力。了解一类新型翻译调控，通过微调蛋白质合成的保真度来增强表型多样性和适应性。