Crystal structures of M11L in the presence and absence of a Bak BH3 domain: structural insight into virus-mediated inhibition of apoptosis

Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research
â—‹Marc Kvansakul Mark Van Delft Walter D Fairlie Jacqui M Gulbis David CS Huang Peter M Colman

Programmed cell death (apoptosis) is a critically important mechanism that enables multicellular organisms to eliminate damaged, infected or unwanted cells. The Bcl-2 family of proteins, which contains both pro- and antiapoptotic members, plays a central role in regulating apoptosis. The two pro-apoptotic members Bax and Bak are activated in response to apoptotic stimuli and play a pivotal role by triggering the release of pro-death factors by a series of unknown conformational events that result in mitochondrial membrane permeabilization (MMP). In healthy cells, Bax and Bak are held in check by anti-apoptotic family members such as Bcl-2, Bcl-XL and Mcl-1. Apoptotic stimuli result in the release of pro-apoptotic BH-3 only proteins (e.g. Bim, Noxa, Bid) that neutralize anti-apoptotic Bcl-2, Bcl-XL and Mcl-1, thus freeing Bak and Bax to cause MMP.
Apoptosis is recognised as a key innate immunity defence mechanism, and viruses have developed different strategies to ensure their survival in the face of host immune responses. Viral Bcl-2 homologs are deployed by Kaposi Sarcoma and Eppstein Barr virus to prevent cells from apoptosis during infection. Myxoma virus (MV), a member of the poxvirus family, encodes a multitude of anti-apoptotic proteins, but lacks an obvious Bcl-2 homologue. The MV protein M11L has been identified as a major virulence factor that locates to the outer mitochondrial membrane, and has been shown to inhibit apoptosis. We have determined the crystal structures of free M11L and M11L in complex with a Bak 26-mer peptide and investigated the anti-apoptotic properties of M11L. Our analysis provides new insight into the mechanism by which MV subverts host apoptosis to ensure virus survival.