RNA functions as an informational, structural and catalytic molecule in cells. However, in most if not all cases where RNA serves as an essential component of a cellular machine, the RNAs collaborate with protein cofactors. Cellular ribonucleoprotein machines for which there is strong evidence that essential active site structures are provided by an RNA include group I and group II introns, RNase P, the spliceosome, the ribosome and telomerase. This non-exhaustive list emphasizes that, although cellular RNA-protein catalysts are relatively rare, they carry out vital processes including RNA biogenesis, polypeptide synthesis and chromosome maintenance. The roles for the protein cofactors have just begun to be explored but include stabilizing and modulating RNA architecture, promoting domain assembly and disassembly, increasing specificity, and allowing regulation. The goal of this project, a collaboration with Dr. Kevin Weeks? laboratory at UNC Chapel Hill, is to determine the crystal structure of a one protein-one RNA ribonucleoprotein catalyst composed of the bI5 group I intron RNA and CBP2 protein from Saccharomyces cerevisiae. A deeper understanding of this simpler system is likely to yield important generalizations in the broad areas of RNA-protein interactions and protein-facilitated RNA catalysis. Insights derived from the crystal structure of the bI5/CBP2 complex will increase our understanding of many medically important processes involving essential cellular machines comprised of RNA and protein components. In addition, catalytic RNAs, or ribozymes, represent a promising approach to gene therapy. In vivo, the activities of engineered ribozymes will be modulated by interactions with endogenous cellular proteins, a phenomenon that must be understood to develop successful RNA therapeutics. This project is in its infancy, but Dr. Weeks? laboratory has been successful at producing milligram quantities of CBP2 protein in E. coli and stoichiometric quantities of the corresponding RNA.
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