Structural and biochemical studies are proposed to examine protein- protein and protein-lipid interactions involved in viral budding and viral maturation. The focus is on the plus-strand RNA viruses, which either cause human disease or are closely related to viruses which cause human disease. The budding process and nucleocapsid stabilization will be investigated by NMR and other methods for alphavirus, hepatitis C virus, rubella virus, and yellow fever virus, the most simple enveloped viruses. Structural features important for capsid stabilization and maturation will be investigated by NMR for Rous sarcoma virus (RSV), a structurally more complex retrovirus. Specific objectives are to understand the importance of the capsid-nucleocapsid region of the RSV Gag protein by determining 3-dimensional solution structures of various RSV protein constructs, and characterizing interdomain interactions for the C-terminal domain of capsid (CA) protein, the nucleocapsid (NC) protein, and the capsid-nucleocapsid core particles and the transmembrane E2- glycoprotein has been proposed and will be tested by biochemical and NMR experiments. Further studies to investigate nucleocapsid stability are also proposed for yellow fever virus (YFV), hepatitis C virus (HCV), and rubella virus (RUBV) using NMR methods combined with mutagenesis results. Results from the studies proposed in this project, coupled with results from molecular genetics and crystallography proposed elsewhere in the Program Project, will enhance our understanding of the structural and physical basis underlying viral assembly.
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