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Structural and Functional Insight into Canarypox Virus CNP058 Mediated Regulation of Apoptosis

Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
Author to whom correspondence should be addressed.
Academic Editor: Eric O. Freed
Viruses 2017, 9(10), 305;
Received: 1 October 2017 / Revised: 15 October 2017 / Accepted: 18 October 2017 / Published: 20 October 2017
(This article belongs to the Special Issue Viral Infection and Apoptosis)
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Programmed cell death or apoptosis is an important component of host defense systems against viral infection. The B-cell lymphoma 2 (Bcl-2) proteins family is the main arbiter of mitochondrially mediated apoptosis, and viruses have evolved sequence and structural mimics of Bcl-2 to subvert premature host cell apoptosis in response to viral infection. The sequencing of the canarypox virus genome identified a putative pro-survival Bcl-2 protein, CNP058. However, a role in apoptosis inhibition for CNP058 has not been identified to date. Here, we report that CNP058 is able to bind several host cell pro-death Bcl-2 proteins, including Bak and Bax, as well as several BH3 only-proteins including Bim, Bid, Bmf, Noxa, Puma, and Hrk with high to moderate affinities. We then defined the structural basis for CNP058 binding to pro-death Bcl-2 proteins by determining the crystal structure of CNP058 bound to Bim BH3. CNP058 adopts the conserved Bcl-2 like fold observed in cellular pro-survival Bcl-2 proteins, and utilizes the canonical ligand binding groove to bind Bim BH3. We then demonstrate that CNP058 is a potent inhibitor of ultraviolet (UV) induced apoptosis in a cell culture model. Our findings suggest that CNP058 is a potent inhibitor of apoptosis that is able to bind to BH3 domain peptides from a broad range of pro-death Bcl-2 proteins, and may play a key role in countering premature host apoptosis. View Full-Text
Keywords: poxvirus; avipoxvirus; apoptosis; X-ray crystallography; isothermal titration calorimetry; Bcl-2 poxvirus; avipoxvirus; apoptosis; X-ray crystallography; isothermal titration calorimetry; Bcl-2

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Anasir, M.I.; Baxter, A.A.; Poon, I.K.H.; Hulett, M.D.; Kvansakul, M. Structural and Functional Insight into Canarypox Virus CNP058 Mediated Regulation of Apoptosis. Viruses 2017, 9, 305.

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