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.
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