Browsing by Author "Caria, S"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    Grouper iridovirus GIV66 is a Bcl-2 protein that inhibits apoptosis by exclusively sequestering Bim
    (Society of Crystallographers in Australia and New Zealand, 2017-12-03) Banjara, S; Mao, J; Ryan, TM; Caria, S; Kvansakul, M
    Programmed cell death or apoptosis is a critical mechanism for the controlled removal of damaged or infected cells, and proteins of the Bcl-2 family are important arbiters of this process. Viruses have been shown to encode for functional and structural homologues of Bcl-2 to counter premature host cell apoptosis to ensure viral proliferation and/or survival. Grouper iridovirus (GIV) is a large DNA virus belonging to the iridoviridae family that harbours GIV66, a putative Bcl-2 like protein. GIV66 is a mitochondrially localised inhibitor of apoptosis, however, the molecular and structural basis of apoptosis inhibition is currently not understood. To gain insight into the mechanism of action we systematically evaluated the ability of GIV66 to bind peptides spanning the BH3 domain of proapoptotic Bcl-2 family members. Our data reveal that GIV66 harbours an unusually high level of specificity for pro-apoptotic Bcl-2, and only engages with Bim. We then determined crystal structures of both GIV66 on its own as well as bound to Bim BH3. Unexpectedly, GIV66 forms dimers via a novel interface that occludes access to the canonical Bcl-2 ligand binding groove, which break apart upon Bim binding. These data suggest that GIV66 dimerisation impacts on the ability of GIV66 to bind and select host pro-death Bcl-2 protein. Our findings provide a mechanistic understanding for the potent anti-apoptotic activity of GIV66 by identifying it as the first single specificity pro-survival Bcl2 protein, and demonstrating the pivotal role of Bim for GIV mediated inhibition of apoptosis.