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J. Biol. Chem., Vol. 281, Issue 32, 22517-22526, August 11, 2006

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Variation in Ligand Binding Specificities of a Novel Class of Poxvirus-encoded Tumor Necrosis Factor-binding Protein^*

Masmudur M. Rahman, John W. Barrett, Peter Brouckaert, and Grant McFadden¹

From the BioTherapeutics Research Group, Robarts Research Institute and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6G2V4, Canada and the Molecular Pathophysiology and Experimental Therapy Unit, Department for Molecular Biomedical Research, Ghent University and VIB, Technologiepark 927, B-9052 Ghent, Belgium

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 (K_D, 43 pM) compared with monkey (K_D, 120 pM) whereas for YMTV-2L, the affinities were reversed (human TNF K_D, 440 pM; monkey TNF K_D, 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.

Received for publication, May 15, 2006 , and in revised form, June 16, 2006.

^* This work was supported by the National Cancer Institute of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and Table S1.

¹ Holds a Canada Research Chair in Molecular Virology and is an International Scholar of The Howard Hughes Medical Institute. To whom correspondence should be addressed: BioTherapeutics Research Group, Robarts Research Inst., SDRI Rm. 133, 1400 Western Rd., London, ON N6G2V4, Canada. Tel.: 519-663-3184; Fax: 519-663-3715; E-mail: mcfadden{at}robarts.ca.

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