Download MendeleyStructural Insight Into Bh3-Domain Binding of Vaccinia Virus Anti-Apoptotic F1L.
Campbell, S., Thibault, J., Mehta, N., Colman, P.M., Barry, M., Kvansakul, M.(2014) J Virol 88: 8667
- PubMed: 24850748
- DOI: https://doi.org/10.1128/JVI.01092-14
- Primary Citation of Related Structures:
4D2L, 4D2M - PubMed Abstract:
Apoptosis is a tightly regulated process that plays a crucial role in the removal of virus-infected cells, a process controlled by both pro- and antiapoptotic members of the Bcl-2 family. The proapoptotic proteins Bak and Bax are regulated by antiapoptotic Bcl-2 proteins and are also activated by a subset of proteins known as BH3-only proteins that perform dual functions by directly activating Bak and Bax or by sequestering and neutralizing antiapoptotic family members. Numerous viruses express proteins that prevent premature host cell apoptosis. Vaccinia virus encodes F1L, an antiapoptotic protein essential for survival of infected cells that bears no discernible sequence homology to mammalian cell death inhibitors. Despite the limited sequence similarities, F1L has been shown to adopt a novel dimeric Bcl-2-like fold that enables hetero-oligomeric binding to both Bak and the proapoptotic BH3-only protein Bim that ultimately prevents Bak and Bax homo-oligomerization. However, no structural data on the mode of engagement of F1L and its Bcl-2 counterparts are available. Here we solved the crystal structures of F1L in complex with two ligands, Bim and Bak. Our structures indicate that F1L can engage two BH3 ligands simultaneously via the canonical Bcl-2 ligand binding grooves. Furthermore, by structure-guided mutagenesis, we generated point mutations within the binding pocket of F1L in order to elucidate the residues responsible for both Bim and Bak binding and prevention of apoptosis. We propose that the sequestration of Bim by F1L is primarily responsible for preventing apoptosis during vaccinia virus infection.
Organizational Affiliation:
Li Ka Shing Institute for Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
