title: Structural Insight into African Swine Fever Virus A179L-Mediated Inhibition of Apoptosis.
abstract: Programmed cell death is a tightly controlled process critical for the removal of damaged or infected cells. Pro- and antiapoptotic proteins of the Bcl-2 family are pivotal mediators of this process. African swine fever virus (ASFV) is a large DNA virus, the only member of theAsfarviridaefamily, and harbors A179L, a putative Bcl-2 like protein. A179L has been shown to bind to several proapoptotic Bcl-2 proteins; however, the hierarchy of binding and the structural basis for apoptosis inhibition are currently not understood. We systematically evaluated the ability of A179L to bind proapoptotic Bcl-2 family members and show that A179L is the first antiapoptotic Bcl-2 protein to bind to all major death-inducing mammalian Bcl-2 proteins. We then defined the structural basis for apoptosis inhibition of A179L by determining the crystal structures of A179L bound to both Bid and Bax BH3 motifs. Our findings provide a mechanistic understanding for the potent antiapoptotic activity of A179L by identifying it as the first panprodeath Bcl-2 binder and serve as a platform for more-detailed investigations into the role of A179L during ASFV infection.IMPORTANCENumerous viruses have acquired strategies to subvert apoptosis by encoding proteins capable of sequestering proapoptotic host proteins. African swine fever virus (ASFV), a large DNA virus and the only member of theAsfarviridaefamily, encodes the protein A179L, which functions to prevent apoptosis. We show that A179L is unusual among antiapoptotic Bcl-2 proteins in being able to physically bind to all core death-inducing mammalian Bcl-2 proteins. Currently, little is known regarding the molecular interactions between A179L and the proapoptotic Bcl-2 members. Using the crystal structures of A179L bound to two of the identified proapoptotic Bcl-2 proteins, Bid and Bax, we now provide a three-dimensional (3D) view of how A179L sequesters host proapoptotic proteins, which is crucial for subverting premature host cell apoptosis.
authors.affiliation: Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Suresh
authors.initials: S
authors.lastname: Banjara
authors.affiliation: Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Sofia
authors.initials: S
authors.lastname: Caria
authors.affiliation: Pirbright Institute, Pirbright, Surrey, England.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Dixon
authors.affiliation: Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia m.hinds@latrobe.edu.au m.kvansakul@latrobe.edu.au.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hinds
authors.affiliation: Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia m.hinds@latrobe.edu.au m.kvansakul@latrobe.edu.au.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0003-2639-2498
authors.initials: M
authors.lastname: Kvansakul
mesh_terms: D000358:African Swine Fever Virus / Q000472:pathogenicity*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D054884:Host-Pathogen Interactions; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013552:Swine; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D014764:Viral Proteins
keywords: ASFV; Bax family; Bcl-2; X-ray crystallography; apoptosis