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Title | Structural basis of Deerpox virus-mediated inhibition of apoptosis. |
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Journal, issue, pages | Acta Crystallogr D Biol Crystallogr, Vol. 71, Issue Pt 8, Page 1593-1603, Year 2015 |
Publish date | Jul 28, 2015 |
Authors | Denis R Burton / Sofia Caria / Bevan Marshall / Michele Barry / Marc Kvansakul / |
PubMed 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 ...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. |
External links | Acta Crystallogr D Biol Crystallogr / PubMed:26249341 |
Methods | SAS (X-ray synchrotron) / X-ray diffraction |
Resolution | 2.3 - 3 Å |
Structure data | SASDAD8: Antiapoptotic membrane protein, (DpV84gp022) Deerpox virus PDB-4uf1: PDB-4uf2: PDB-4uf3: |
Chemicals | ChemComp-SO4: ChemComp-HOH: |
Source |
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Keywords | VIRAL PROTEIN / DEERPOX VIRUS / APOPTOSIS / BCL-2 / BAK BH3 / BAX BH3 / DPV022 / BIM BH3 |