The role of the rabies P protein in host cell evasion and viral replication

  • Project Leader

    Associate Professor Paul Gooley
    T: +61 0437 835 059 (moblile)
    +61 3 834 42273

    E: prg@unimelb.edu.au
    W: Personal web page

    Location: Rm 231, Level 02, Bio21 Institute, 30 Flemington Rd

Project Details

diagram mapping the STAT1 binding site on the rabies P protein
Figure 1: Mapping the STAT1 binding site on the rabies P protein


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.

Collaborators

Dr Greg Moseley (Monash), Spencer Williams (Chemistry, UoM)

Research Opportunities

This research project is available to PhD, Honours students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Group

Gooley laboratory: Structural biology of disease



Faculty Research Themes

Infection and Immunology

School Research Themes

Infection & Immunity, Cellular Imaging & Structural Biology



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Biochemistry and Molecular Biology

Unit / Centre

Gooley laboratory: Structural biology of disease