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Title | Structural basis of apoptosis inhibition by the fowlpox virus protein FPV039. |
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Journal, issue, pages | J Biol Chem, Vol. 292, Issue 22, Page 9010-9021, Year 2017 |
Publish date | Jun 2, 2017 |
Authors | Mohd Ishtiaq Anasir / Sofia Caria / Michael A Skinner / Marc Kvansakul / |
PubMed Abstract | Programmed cell death or apoptosis of infected host cells is an important defense mechanism in response to viral infections. This process is regulated by proapoptotic and prosurvival members of the B- ...Programmed cell death or apoptosis of infected host cells is an important defense mechanism in response to viral infections. This process is regulated by proapoptotic and prosurvival members of the B-cell lymphoma 2 (Bcl-2) protein family. To counter premature death of a virus-infected cell, poxviruses use a range of different molecular strategies including the mimicry of prosurvival Bcl-2 proteins. One such viral prosurvival protein is the fowlpox virus protein FPV039, which is a potent apoptosis inhibitor, but the precise molecular mechanism by which FPV039 inhibits apoptosis is unknown. To understand how fowlpox virus inhibits apoptosis, we examined FPV039 using isothermal titration calorimetry, small-angle X-ray scattering, and X-ray crystallography. Here, we report that the fowlpox virus prosurvival protein FPV039 promiscuously binds to cellular proapoptotic Bcl-2 and engages all major proapoptotic Bcl-2 proteins. Unlike other identified viral Bcl-2 proteins to date, FPV039 engaged with cellular proapoptotic Bcl-2 with affinities comparable with those of Bcl-2's endogenous cellular counterparts. Structural studies revealed that FPV039 adopts the conserved Bcl-2 fold observed in cellular prosurvival Bcl-2 proteins and closely mimics the structure of the prosurvival Bcl-2 family protein Mcl-1. Our findings suggest that FPV039 is a pan-Bcl-2 protein inhibitor that can engage all host BH3-only proteins, as well as Bcl-2-associated X, apoptosis regulator (Bax) and Bcl-2 antagonist/killer (Bak) proteins to inhibit premature apoptosis of an infected host cell. This work therefore provides a mechanistic platform to better understand FPV039-mediated apoptosis inhibition. |
External links | J Biol Chem / PubMed:28411240 / PubMed Central |
Methods | SAS (X-ray synchrotron) / X-ray diffraction |
Resolution | 1.35 - 1.65 Å |
Structure data | SASDC63: Fowlpox Virus FPV039 antiapoptotic Bcl-2 viral protein in complex with BaK BH3 peptide (FPV039:BAK) PDB-5tzp: PDB-5tzq: |
Chemicals | ChemComp-EDO: ChemComp-SO4: ChemComp-HOH: |
Source |
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Keywords | APOPTOSIS / Bcl-2 / fowlpox / poxvirus / BH3-only / fowlpox virus / Bmf |