Grouper iridovirus mediated inhibition of apoptosis
- Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
- SAXS/WAXS, Australian Synchrotron, 800 Blackburn Road, Clayton, VIC 3168, Australia.
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 homologs 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 harbors GIV66, a putative Bcl-2 like protein. GIV66 is a mitochondrially localized 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 pro-apoptotic Bcl-2 family members. Our data reveal that GIV66 harbors an unusually high level of specificity for pro-apoptotic Bcl-2, and only displays affinity for Bim. We then determined crystal structures of both GIV66 on its own as well as bound to Bim BH3. Unexpectedly, GIV66 forms dimers via an interface that results in occluded access to the canonical Bcl-2 ligand binding groove, which breaks apart upon Bim binding. These data suggest that GIV66 dimerization may impacts on the ability of GIV66 to bind 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 Bcl-2 protein, and identifying a pivotal role of Bim for GIV mediated inhibition of apoptosis.