Structure and function of RNase P

描述(申请人提供)：人类细胞依赖RNA在信息传递和其他生物分子的合成中发挥中心作用。在这些过程中的几个关键点上，RNA本身起到了催化剂的作用。由于它们的基本作用，这些分子是抗癌和抗病毒治疗的重要靶点。然而，细胞和病毒中的RNA需要特定蛋白质的结合才能发挥作用。因此，要完全理解RNA的生理学，既需要了解RNA分子本身的结构和催化特性，也需要了解蛋白质结合在激活和调节其生物活性方面所起的作用。然而，我们对RNA催化机制的了解还在不断加深，大多数RNA-蛋白质复合体组装过程中构象变化的范围和功能效应还很难实现。 我们的研究重点是了解细菌RNaseP的RNA和蛋白质亚基是如何共同作用实现生物催化的。RNaseP是一种普遍存在的高度保守的核糖核蛋白酶，它能产生tRNAs的成熟5‘端。这种核糖核蛋白由一个单一的蛋白质与一个更大的催化RNA亚单位结合组成，称为P RNA，因此是探索RNA催化的基本方面以及RNA和蛋白质的协调生物功能的优秀模型系统。我们正在利用这个系统来解决三个基本问题：1.RNaseP催化磷酸二酯水解的机制是什么？2.RNA和蛋白质亚单位是如何协同实现催化作用的？以及，3.RNA和蛋白质亚单位折叠成功能复合体的途径是什么？这些问题的答案将有助于我们理解生物催化和核糖核蛋白的功能，并从长远来看，为靶向RNA的基于抑制剂的治疗提供基础。

DESCRIPTION (provided by applicant): Human cells depend on RNA to perform central roles in information transfer and the synthesis of other biomolecules. At several critical points in these processes RNA itself acts as a catalyst. Because of their essential role, these molecules are important targets for anti-cancer and anti-viral therapies. However, the RNAs in cells and viruses require the binding of specific proteins to function. Thus, a complete understanding of physiology of RNA requires both an understanding of the structural and catalytic features of the RNA molecules themselves, as well as the roles that protein binding plays in activating and modulating their biological activity. However, our understanding of RNA catalytic mechanism is still emerging and the range and functional effects of conformational changes in the assembly of most RNA-protein complexes has been difficult to achieve. Our investigations focus on understanding how the RNA and protein subunits of bacterial RNase P work together to achieve biological catalysis. RNase P is a ubiquitous and highly conserved ribonucleoprotein enzyme that generates the mature 5' ends of tRNAs. This ribonucleoprotein consists of a single protein bound to a larger catalytic RNA subunit termed P RNA, and is thus an excellent model system for exploring fundamental aspects of RNA catalysis and the coordinated biological function of RNA and protein. We are using this system to address three fundamental questions: 1. What is the mechanism of RNase P catalyzed phosphodiester hydrolysis?; 2. How do the RNA and protein subunits collaborate to achieve catalysis?; and, 3. What is the pathway by which the RNA and protein subunits fold into a functional complex? The answers to these questions will contribute to our understanding of biological catalysis and ribonucleoprotein function and in the long term provide the basis for inhibitor-based therapeutics that target RNAs.