5VMN

Crystal structure of grouper iridovirus GIV66

Summary for 5VMN

• Entry DOI: 10.2210/pdb5vmn/pdb
• Related: 5VMO
• Descriptor: Bak protein, NITRATE ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: apoptosis, bcl-2, iridovirus, grouper, viral protein
• Biological source: Grouper iridovirus
• Total number of polymer chains: 1
• Total formula weight: 15812.42

Authors

Banjara, S.,Kvansakul, M. (deposition date: 2017-04-27, release date: 2018-03-07, Last modification date: 2024-03-13)

Primary citation

Banjara, S.,Mao, J.,Ryan, T.M.,Caria, S.,Kvansakul, M.
Grouper iridovirus GIV66 is a Bcl-2 protein that inhibits apoptosis by exclusively sequestering Bim.
J. Biol. Chem., 293:5464-5477, 2018

PubMed Abstract: 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 basis 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 Bcl-2-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 signaling. 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 in GIV-mediated inhibition of apoptosis.

PubMed: 29483196
DOI: 10.1074/jbc.RA117.000591

Experimental method

X-RAY DIFFRACTION (1.65 Å)