期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 10, 页码 5991-6002出版社
ELSEVIER
DOI: 10.1074/jbc.M114.624650
关键词
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资金
- Wellcome Trust Principal Research Fellowship [090315]
- Sir Henry Dale Fellowship - Wellcome Trust [098406/Z/12/Z]
- Sir Henry Dale Fellowship - Royal Society [098406/Z/12/Z]
- United Kingdom Medical Research Council [G1000099]
- Wellcome Trust [098406/Z/12/Z] Funding Source: Wellcome Trust
- MRC [G1000099] Funding Source: UKRI
- Medical Research Council [G1000099] Funding Source: researchfish
Vaccinia virus (VACV) encodes several proteins that inhibit activation of the proinflammatory transcription factor nuclear factor kappa B (NF-kappa B). VACV protein A49 prevents translocation of NF-kappa B to the nucleus by sequestering cellular beta-TrCP, a protein required for the degradation of the inhibitor of kappa B. 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 angstrom 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 beta-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.
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