title: Structural basis of Deerpox virus-mediated inhibition of apoptosis.
abstract: Apoptosis is a key innate defence mechanism to eliminate virally infected cells. To counteract premature host-cell apoptosis, poxviruses have evolved numerous molecular strategies, including the use of Bcl-2 proteins, to ensure their own survival. Here, it is reported that the Deerpox virus inhibitor of apoptosis, DPV022, only engages a highly restricted set of death-inducing Bcl-2 proteins, including Bim, Bax and Bak, with modest affinities. Structural analysis reveals that DPV022 adopts a Bcl-2 fold with a dimeric domain-swapped topology and binds pro-death Bcl-2 proteins via two conserved ligand-binding grooves found on opposite sides of the dimer. Structures of DPV022 bound to Bim, Bak and Bax BH3 domains reveal that a partial obstruction of the binding groove is likely to be responsible for the modest affinities of DPV022 for BH3 domains. These findings reveal that domain-swapped dimeric Bcl-2 folds are not unusual and may be found more widely in viruses. Furthermore, the modest affinities of DPV022 for pro-death Bcl-2 proteins suggest that two distinct classes of anti-apoptotic viral Bcl-2 proteins exist: those that are monomeric and tightly bind a range of death-inducing Bcl-2 proteins, and others such as DPV022 that are dimeric and only bind a very limited number of death-inducing Bcl-2 proteins with modest affinities.
authors.affiliation: Department of Biochemistry, La Trobe University, Melbourne, VIC 3058, Australia.
authors.forename: Denis R
authors.initials: DR
authors.lastname: Burton
authors.affiliation: Department of Biochemistry, La Trobe University, Melbourne, VIC 3058, Australia.
authors.forename: Sofia
authors.initials: S
authors.lastname: Caria
authors.affiliation: Department of Biochemistry, La Trobe University, Melbourne, VIC 3058, Australia.
authors.forename: Bevan
authors.initials: B
authors.lastname: Marshall
authors.affiliation: Li Ka Shing Institute for Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Michele
authors.initials: M
authors.lastname: Barry
authors.affiliation: Department of Biochemistry, La Trobe University, Melbourne, VIC 3058, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Kvansakul
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D018360:Crystallography, X-Ray; D054884:Host-Pathogen Interactions; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011212:Poxviridae / Q000737:chemistry* / Q000378:metabolism; D011213:Poxviridae Infections / Q000378:metabolism / Q000821:virology*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins
keywords: Bcl-2; X-ray crystallography; apoptosis; poxvirus