The role of the rabies P protein in host cell evasion and viral replication
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The rabies virus phosphoprotein (P protein) has central roles in evading the host cell's antiviral mechanisms and in viral replication. The P protein neutralizes the host innate defences by acting to antagonize type I interferon (IFN), thereby preventing both transcriptional induction of IFN and expression of IFN-stimulated genes in target cells. Specifically, rabies P protein inhibits IFN-α and IFN-γ mediated transcriptional responses and subsequently prevents nuclear accumulation of the signal transducer and activator of transcription 1 (STAT1α) to overcome an antiviral state of the infected cells. We have identified a region of the P protein C-terminal domain that appears to be the critical interacting site for STAT1α binding. To obtain insight into the mechanism by which P-protein interacts with STAT1α, one project aims to determine the interacting residues/sites of the C-terminal domain of P protein and STAT1α and the structure of the complex.
The P protein is also essential for viral replication. The N-terminal region of the P protein binds to the viral RNA polymerase (called L protein), while the C-terminal domain of the P protein binds to the RNA loaded viral N protein. Hence P protein serves as an effector for RNA synthesis. Therefore other projects aim to understand the structures of the regions of L and N proteins bound to P protein. Towards this goal we have taken a disordered loop of the N protein and shown it binds to the C-terminal domain of P protein and we are currently defining its structure and nature of interaction. Importantly, like many viral proteins the P protein has large regions that are intrinsically unstructured, and the P protein exits as five isoforms, consistent with the multiple roles of P protein. Therefore we wish to understand the structure of apo P protein, the isoforms, and P protein bound to its many partners. Understanding the structural diversity, and its limits, is directed towards designing novel antivirals.
Dr Greg Moseley (Monash), Spencer Williams (Chemistry, UoM)
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