Structural Dynamics of Translation

分子生物学的中心法则是DNA被用来制造信使核糖核酸，而信使核糖核酸又被用来制造 蛋白质。信使RNA(信使核糖核酸)到蛋白质的翻译是每个活细胞的核心生理过程 由核糖体催化，结构复杂，动态的大分子机器。失调症 翻译在包括癌症在内的许多人类疾病中扮演着重要的角色。虽然有些基本面 尽管蛋白质合成的许多分子细节已经被揭示，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比其他的更有效地被翻译成数量级， 以及信使核糖核酸结构如何调节蛋白质的合成。我的实验室研究的分子机制是 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 翻译规则。我们使用单分子显微镜和生化方法来解决 以下问题：(1)核糖体小亚基在寻找核糖体的起始部位时是如何沿mR-NA移动的 真核生物中的翻译启动？(Ii)信使核糖核酸和分子内的内在紧密度是如何 由mRNA的5‘和3’非翻译区(UTRs)形成的碱基相互作用调节效率 真核生物的蛋白质合成？(Iii)信使核糖体的茎环结构如何诱导核糖体翻译 停顿控制着细菌、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和新冠肺炎大流行的原因--SARS-CoV-2？(四) 真核核糖体的结构动力学(特别是小核糖体之间的旋转运动)是怎样的 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 为建立蛋白质合成的分子机制做出了实质性贡献，并提供了基础 用于未来抗病毒和癌症治疗的发展。

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.