Structural insight into tanapoxvirus-mediated inhibition of apoptosis.
Chathura D SuraweeraMohd Ishtiaq AnasirSrishti ChughAirah JavorskyRachael E ImpeyMohammad Hasan ZadehTatiana P Soares da CostaMark G HindsMarc KvansakulPublished in: The FEBS journal (2020)
Premature programmed cell death or apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Tanapoxvirus (TANV) is a large double-stranded DNA virus belonging to the poxviridae that causes mild monkeypox-like infections in humans and primates. TANV encodes for a putative apoptosis inhibitory protein 16L. We show that TANV16L is able to bind to a range of peptides spanning the BH3 motif of human proapoptotic Bcl-2 proteins and is able to counter growth arrest of yeast induced by human Bak and Bax. We then determined the crystal structures of TANV16L bound to three identified interactors, Bax, Bim and Puma BH3. TANV16L adopts a globular Bcl-2 fold comprising 7 α-helices and utilizes the canonical Bcl-2 binding groove to engage proapoptotic host cell Bcl-2 proteins. Unexpectedly, TANV16L is able to adopt both a monomeric and a domain-swapped dimeric topology where the α1 helix from one protomer is swapped into a neighbouring unit. Despite adopting two different oligomeric forms, the canonical ligand binding groove in TANV16L remains unchanged from monomer to domain-swapped dimer. Our results provide a structural and mechanistic basis for tanapoxvirus-mediated inhibition of host cell apoptosis and reveal the capacity of Bcl-2 proteins to adopt differential oligomeric states whilst maintaining the canonical ligand binding groove in an unchanged state. DATABASE: Structural data are available in the Protein Data Bank (PDB) under the accession numbers 6TPQ, 6TQQ and 6TRR.
Keyphrases
- cell cycle arrest
- induced apoptosis
- endoplasmic reticulum stress
- oxidative stress
- cell death
- endothelial cells
- binding protein
- pi k akt
- single cell
- induced pluripotent stem cells
- amino acid
- emergency department
- pluripotent stem cells
- big data
- cell proliferation
- circulating tumor
- stem cells
- single molecule
- genome wide
- dna methylation
- machine learning
- dna binding
- multidrug resistant
- data analysis
- gene expression
- cell cycle
- mesenchymal stem cells
- molecularly imprinted
- transcription factor
- tandem mass spectrometry