Banjara, S.; Shimmon, G.L.; Dixon, L.K.; Netherton, C.L.; Hinds, M.G.; Kvansakul, M. Crystal Structure of African Swine Fever Virus A179L with the Autophagy Regulator Beclin. Viruses2019, 11, 789.
Banjara, S.; Shimmon, G.L.; Dixon, L.K.; Netherton, C.L.; Hinds, M.G.; Kvansakul, M. Crystal Structure of African Swine Fever Virus A179L with the Autophagy Regulator Beclin. Viruses 2019, 11, 789.
Banjara, S.; Shimmon, G.L.; Dixon, L.K.; Netherton, C.L.; Hinds, M.G.; Kvansakul, M. Crystal Structure of African Swine Fever Virus A179L with the Autophagy Regulator Beclin. Viruses2019, 11, 789.
Banjara, S.; Shimmon, G.L.; Dixon, L.K.; Netherton, C.L.; Hinds, M.G.; Kvansakul, M. Crystal Structure of African Swine Fever Virus A179L with the Autophagy Regulator Beclin. Viruses 2019, 11, 789.
Abstract
Subversion of programmed cell death-based host defence systems is a prominent feature of infections by large DNA viruses. African swine fever virus (ASFV) is a large DNA virus and sole member of the Asfarviridae family that harbors the B-cell lymphoma 2 or Bcl-2 homolog A179L. A179L has been shown to bind to a range of cell death inducing host proteins including pro-apoptotic Bcl-2 proteins as well as the autophagy regulator Beclin. Here we report the crystal structure of A179L bound to the Beclin BH3 motif. A179L engages Beclin using the same canonical ligand binding groove that is utilized to bind to pro-apoptotic Bcl-2 proteins. The mode of binding of Beclin to A179L mirrors that of Beclin binding to human Bcl-2 and Bcl-xL as well as murine gamma-herpesvirus 68. Introduction of bulky hydrophobic residues into the A179L ligand binding groove via site directed mutagenesis ablates binding of Beclin to A179L, leading to a loss of ability of A179L to modulate autophagosome formation in Vero cells during starvation. Our findings provide a mechanistic understanding for the potent autophagy inhibitory activity of A179L and serve as a platform for more detailed investigations into the role of autophagy during ASFV infection.
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