4d5r
Structure of N-terminally truncated A49 from Vaccinia Virus Western Reserve
Structural highlights
FunctionA49_VACCW Plays a role in the inhibition of host NF-kappa-B activation. Interacts with host BTRC and thereby diminishes ubiquitination of NF-kappa-B inhibitor alpha/NFKBIA. This stabilizes NFKBIA and its interaction with NF-kappaB, so retaining p65/RELA in the cytoplasm and preventing NF-kappa-B-dependent gene expression.[1] Publication Abstract from PubMedVaccinia virus (VACV) encodes several proteins that inhibit activation of the pro-inflammatory transcription factor nuclear factor kappaB (NF-kappaB). VACV protein A49 prevents translocation of NF-kappaB to the nucleus by sequestering cellular beta-TrCP, a protein required for the degradation of the inhibitor of kappaB. A49 does not share overall sequence similarity with any protein of known structure or function. We solved the crystal structure of A49 from VACV Western Reserve to 1.8 A resolution and showed, surprisingly, that A49 has the same three-dimensional fold as Bcl-2 family proteins despite lacking identifiable sequence similarity. While Bcl-2 family members characteristically modulate cellular apoptosis, A49 lacks a surface groove suitable for binding BH3 peptides and does not bind pro-apoptotic Bcl-2 family proteins Bax or Bak. The N-terminal 17 residues of A49 do not adopt a single well-ordered conformation, consistent with their proposed role in binding beta-TrCP. While pairs of A49 molecules interact symmetrically via a large hydrophobic surface in crystallo, A49 does not dimerize in solution or in cells and we propose that this hydrophobic interaction surface may mediate binding to a yet-undefined cellular partner. A49 represents the eleventh VACV Bcl 2 family protein and, despite these proteins sharing very low sequence identity, structure-based phylogenetic analysis shows that all poxvirus Bcl-2 proteins are structurally more similar to each other than they are to any cellular or herpes virus Bcl-2 proteins. This is consistent with duplication and diversification of a single BCL2 family gene acquired by an ancestral poxvirus. Vaccinia Virus Protein A49 is an Unexpected Member of the B-cell Lymphoma (Bcl)-2 Protein Family.,Neidel S, Maluquer de Motes C, Mansur DS, Strnadova P, Smith GL, Graham SC J Biol Chem. 2015 Jan 20. pii: jbc.M114.624650. PMID:25605733[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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