title: Variation in ligand binding specificities of a novel class of poxvirus-encoded tumor necrosis factor-binding protein.
abstract: The Yatapoxviruses encode a distinct class of secreted TNF-binding protein (TNF-BP) that resembles an MHC class I heavy chain but distinct from any other known TNF inhibitor. Characterization of these viral TNF inhibitors from Tanapox virus, Yaba monkey tumor virus (YMTV) and a closely related version from Swinepox virus revealed dramatically differential TNF binding specificities for different mammalian species. The Tanapox virus 2L protein (TPV-2L) formed inhibitory complexes with human TNF, and interacted with monkey and canine TNF with high affinity but rabbit TNF with low affinity. On the other hand, YMTV-2L bound human and monkey TNF with high affinity but rabbit TNF with only low affinity. The TNF-BP from swinepox virus (SPV003/148) only interacted with porcine TNF with high affinity. The observed TNF binding analysis mirrored the biological activity of these TNF-binding protein to block TNF-induced cellular cytolysis. TPV-2L and YMTV-2L also inhibited the human TNF-mediated signaling in cells but TPV-2L exhibited higher affinity for human TNF (KD, 43 pm) compared with monkey (KD, 120 pm) whereas for YMTV-2L, the affinities were reversed (human TNF KD, 440 pm; monkey TNF KD, 230 pm). The interaction domain of human TNF with TNF-binding proteins is significantly different from that of TNFRs, as determined using human TNF mutants. We conclude that these poxvirus TNF-binding proteins represent a new class of TNF inhibitors and are distinct from the viral TNF receptor homologues characterized to date.
authors.affiliation: BioTherapeutics Research Group, Robarts Research Institute and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6G2V4, Canada.
authors.forename: Masmudur M
authors.initials: MM
authors.lastname: Rahman
authors.forename: John W
authors.initials: JW
authors.lastname: Barrett
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
mesh_terms: D000818:Animals; D000882:Haplorhini; D006801:Humans; D007313:Insecta; D007700:Kinetics; D008024:Ligands; D011212:Poxviridae / Q000378:metabolism*; D011485:Protein Binding; D011817:Rabbits; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D013045:Species Specificity; D013552:Swine; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1