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Open AccessArticle

Crystal Structure of African Swine Fever Virus A179L with the Autophagy Regulator Beclin

1
Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
2
Pirbright Institute, Ash Road, Pirbright, Surrey GU24 0NF, UK
3
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3050, Australia
*
Authors to whom correspondence should be addressed.
Viruses 2019, 11(9), 789; https://doi.org/10.3390/v11090789
Received: 6 August 2019 / Revised: 23 August 2019 / Accepted: 24 August 2019 / Published: 27 August 2019
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 harbours 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 γ-herpesvirus 68. The 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 the 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. View Full-Text
Keywords: Bcl-2; Beclin; autophagy; X-ray crystallography; ASFV Bcl-2; Beclin; autophagy; X-ray crystallography; ASFV
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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.

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