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Structural Dynamics of Translation

翻译的结构动力学

基本信息

批准号：
10755110
负责人：
Dmitri Ermolenko
金额：
$ 2.36万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
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

项目摘要

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 RNAs (mRNAs) into proteins 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 用于制造 mRNA，而 mRNA 又用于制造蛋白质。将信使 RNA (mRNA) 翻译成蛋白质是每个活细胞生理学的核心由核糖体催化，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发挥着重要作用。虽然有一些基础知识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。为了例如，目前尚不清楚为什么某些 mRNA 的翻译效率比其他 mRNA 的效率高出几个数量级，以及 mRNA 结构如何调节蛋白质合成。我的实验室研究分子机制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监管。我们使用单分子显微镜和生化方法来解决以下问题：（i）小核糖体亚基如何沿着 mRNA 移动以寻找起始位点真核生物中的翻译起始？ (ii) mRNA 和分子内的内在致密性如何影响 mRNA 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中蛋白质的合成？ (iii) mRNA茎环结构如何诱导核糖体翻译暂停，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) 和导致 COVID-19 大流行的 SARS-CoV-2？（四）真核核糖体的结构动力学如何（特别是小核糖体之间的旋转运动）和大核糖体亚基）转化为蛋白质合成的复杂过程？我们的研究将为建立蛋白质合成的分子机制做出了重大贡献，并提供了基础为抗病毒和癌症治疗的未来发展。