Structural Dynamics of Translation

翻译的结构动力学

• 批准号: 10205715
• 负责人: Dmitri Ermolenko
• 金额: $ 37.62万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10205715
• 关键词: 2019-nCoV; 3' Untranslated Regions; Address; Antiviral Therapy; Bacteria; Biochemical; COVID-19 pandemic; Cells; Complex; DNA; Development; Eukaryota; Future; Genetic Code; HIV; Human; Immunologic Deficiency Syndromes; Laboratories; Malignant Neoplasms; Messenger RNA; Microscopy; Molecular; Molecular Biology; Molecular Machines; Movement; Organism; Physiology; Play; Process; Protein Biosynthesis; Proteins; Regulation; Ribosomes; Role; Rotation; Signal Transduction; Site; Structure; Translating; Translation Initiation; Translation Process; Translations; Virus; cancer therapy; human disease; single molecule; stem

The Central Dogma of molecular biology is that DNA is used to make mRNA, which in turn is used to make proteins. Central to physiology of every live cell, translation of messenger RNA (mRNA) into protein is catalyzed by the ribosome, structurally complex and dynamic macromolecular machine. Dysregulation of translation plays an important role in a number of human diseases including cancer. While some fundamentals of protein synthesis have been revealed, many molecular details of ribosomal translation remain unknown. For example, it is unclear why some mRNAs are translated orders of magnitude more efficiently than the others, and how mRNA structure regulates protein synthesis. My laboratory investigates molecular mechanisms of translation by studying structural dynamics of the ribosome, and the role of mRNA secondary structure in translation regulation. We use single-molecule microscopy and biochemical approaches to address the following questions: (i) How does the small ribosomal subunit move along mRNA in search for the start site for translation initiation in eukaryotes? (ii) How does the intrinsic compactness of mRNA and intramolecular basepairing interactions formed by the 5' and 3' untranslated regions (UTRs) of mRNA regulate the efficiency of protein synthesis in eukaryotes? (iii) How do mRNA stem-loop structures induce ribosome translation pauses, which control expression of a number of proteins in bacteria, eukaryotes and eukaryotic viruses, including Human Immunodeficiency Virus (HIV) and the cause of the COVID-19 pandemic, SARS-CoV-2? (iv) How are structural dynamics of eukaryotic ribosome (in particular, rotational movements between the small and the large ribosomal subunits) converted into the intricate process of protein synthesis? Our studies will substantially contribute to establishing the molecular mechanisms of protein synthesis, and provide the basis for the future development of antiviral and cancer therapies.

分子生物学的中心法则是，DNA是用来制造mRNA的，mRNA反过来又用来制造 proteins.每个活细胞的生理学中心，信使RNA（mRNA）翻译成蛋白质是 由核糖体催化，结构复杂且动态的大分子机器。失调 翻译在包括癌症在内的许多人类疾病中起着重要作用。虽然一些基本面 尽管蛋白质合成的机制已经被揭示，但核糖体翻译的许多分子细节仍然未知。为 例如，目前还不清楚为什么一些mRNA的翻译效率比其他mRNA高出几个数量级， 以及mRNA结构如何调节蛋白质合成。我的实验室研究了 通过研究核糖体的结构动力学，以及mRNA二级结构在翻译中的作用， 翻译调节我们使用单分子显微镜和生物化学方法来解决 以下问题：（i）核糖体小亚基如何沿着mRNA移动，寻找起始位点， 真核生物的翻译起始(ii)mRNA和分子内的内在紧密性 由mRNA的5'和3'非翻译区（UTR）形成的碱基配对相互作用调节效率 真核生物蛋白质合成的关键(iii)mRNA茎环结构如何诱导核糖体翻译 暂停，其控制细菌、真核生物和真核病毒中许多蛋白质的表达， 包括人类免疫缺陷病毒（HIV）和COVID-19大流行病SARS-CoV-2的原因？（四） 真核生物核糖体的结构动力学（特别是小分子之间的旋转运动） 和大的核糖体亚基）转化为复杂的蛋白质合成过程？我们的研究将 实质上有助于建立蛋白质合成的分子机制，并提供基础 未来抗病毒和癌症治疗的发展。