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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 and Graham, SC (2015) Vaccinia virus protein A49 is an unexpected member of the B-cell Lymphoma (Bcl)-2 protein family. J Biol Chem, 290 (10). pp. 5991-6002.

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Vaccinia virus (VACV) encodes several proteins that inhibit activation of the proinflammatory transcription factor nuclear factor κB (NF-κB). VACV protein A49 prevents translocation of NF-κB to the nucleus by sequestering cellular β-TrCP, a protein required for the degradation of the inhibitor of κB. 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 Å resolution and showed, surprisingly, that A49 has the same three-dimensional fold as Bcl-2 family proteins despite lacking identifiable sequence similarity. Whereas Bcl-2 family members characteristically modulate cellular apoptosis, A49 lacks a surface groove suitable for binding BH3 peptides and does not bind proapoptotic 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 β-TrCP. Whereas 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 herpesvirus Bcl-2 proteins. This is consistent with duplication and diversification of a single BCL2 family gene acquired by an ancestral poxvirus.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Neidel, S
Maluquer de Motes,
Mansur, DS
Strnadova, P
Smith, GL
Graham, SC
Date : 6 March 2015
DOI : 10.1074/jbc.M114.624650
Uncontrolled Keywords : B-cell Lymphoma 2 (Bcl-2) Family, Innate Immunity, NF-κB (NF-KB), Poxvirus, Protein Structure, Structure-based Phylogenetics, Vaccinia Virus, Viral Protein, Apoptosis, Crystallography, X-Ray, HEK293 Cells, Humans, Immunity, Innate, NF-kappa B, Phylogeny, Protein Conformation, Protein Folding, Proto-Oncogene Proteins c-bcl-2, Vaccinia, Vaccinia virus, Viral Proteins
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:28
Last Modified : 24 Jan 2020 19:22

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