5vmo

Publication Abstract from PubMed

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 functional and structural homologs of BCL-2 to counter premature host-cell apoptosis and ensure viral proliferation or survival. Grouper iridovirus (GIV) is a large DNA virus belonging to the Iridoviridae family and harbors GIV66, a putative BCL-2 like protein and mitochondrially localized apoptosis inhibitor. However, the molecular and structural bases of GIV66-mediated apoptosis inhibition is currently not understood. To gain insight into GIV66's mechanism of action, we systematically evaluated its ability to bind peptides spanning the BH3 domain of pro-apoptotic BCL-2 family members. Our results revealed that GIV66 harbors an unusually high level of specificity for pro-apoptotic BCL-2 and displays affinity only for BCL2-like 11 (BCL2L11 or BIM). Using crystal structures of both apo GIV66 and GIV66 bound to the BH3 domain from BIM, we unexpectedly found that 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. This observation suggests that GIV66 dimerization may affect GIV66's ability to bind host pro-death BCL-2 proteins, and enables highly targeted virus directed suppression of host apoptosis signalling. Our findings provide a mechanistic understanding for the potent antiapoptotic activity of GIV66 by identifying it as the first single-specificity, pro-survival BCL-2 protein, and identifying a pivotal role of BIM in GIV-mediated inhibition of apoptosis.

Grouper Iridovirus GIV66 is a Bcl-2 protein that inhibits apoptosis by exclusively sequestering Bim.,Banjara S, Mao J, Ryan TM, Caria S, Kvansakul M J Biol Chem. 2018 Feb 26. pii: RA117.000591. doi: 10.1074/jbc.RA117.000591. PMID:29483196^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.