Structural Studies Of Post-transcriptional Gene Regulati

Environmental Health Sciences

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Abstract

Post-transcriptional regulation of messenger RNA (mRNA) stability and translation are important control points for gene expression. The overall goal of this project is to generate and utilize structural information to enhance our understanding of these processes. We are studying the mechanism of RNA silencing. RNA silencing, the destruction of mRNA by double stranded RNA containing corresponding sequences, has proven to be a useful tool to knock out expression of target genes in eukaryotic cells and may have therapeutic potential. In the past few years, much has been learned about the mechanism by which RNA silencing occurs, including the identification of proteins involved in the process. We are studying the structure of a plant viral protein that suppresses RNAi by binding to the intermediate RNAs, small interferring RNAs (siRNAs), that direct mRNA destruction. We have determined the crystal structure of the p19 protein from Carnation Italian Ringspot Virus in complex with an siRNA. The amino acid sequence of p19 shows no detectable homology to sequences of known structures, yet a part of the protein bears structural similarity to the ribosomal L1 protein. We have also examined the binding specificity of p19 for siRNAs, examining the features of siRNAs that allow recognition by this family of proteins. The p19 protein appears to function in heterologous systems, thus understanding its structure and binding specificity will permit better use of it as a tool for understanding the mechanism of RNA silencing.