Investigation of viral ribonucleic acid recognition by 2'-5'-oligoadenylate synthetases

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A hallmark of many viral infections is the production of foreign nucleic acid molecules that are generated during the life cycle of the virus. Host cells respond to these foreign biomolecules through a variety of mechanisms, including the use of nucleic acid sensor proteins that detect and mount a defensive response against the infection. The McKenna laboratory will focus investigation on an extremely important family of nucleic-acid binding proteins that are central to the recognition of viral infection: 2'-5' oligoadenylate synthetases (OAS). The interaction between OAS enzymes and foreign nucleic acid molecules helps to prevent viral replication by blocking necessary viral protein production. My laboratory will establish a research program to characterize the interactions between naturally occurring viral nucleic acid molecules and OAS enzymes to provide a fundamental understanding of a key mechanism used by host cells to respond to viral invasion. Biophysical characterization will identify key features of viral nucleic acid molecules, and structural biology approaches will generate three-dimensional images of complexes of interest. A novel aspect of the proposed research program is the use of naturally occurring viral nucleic acid molecules as the model systems; most studies to date have employed synthetic nucleic acid molecules that lack key characteristics typical of their viral counterparts. The results expected from the proposed research program will therefore contribute to our understanding of how OAS enzymes distinguish between viral and host-cell nucleic acid molecules. Trainees in the McKenna laboratory have and will continue to benefit from the applicant's expertise in the investigation of protein-nucleic acid interactions and acquire an in-demand skill set given the emerging importance of these interactions in a wide variety of biologically important systems. Highly qualified personnel trained will be well equipped for careers in basic scientific research focused on biotechnology, molecular biology, biochemistry, structural biology, and proteomics.