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Identification of residues in the ectromelia virus gamma interferon-binding protein involved in expanded species specificity

¹ Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, St Louis, MO 63104, USA
² Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA

Correspondence
R. Mark L. Buller
bullerrm{at}slu.edu

Gamma interferon (IFN-) production is important in the host response to, and recovery from, infection with Ectromelia virus (ECTV) and Vaccinia virus (VACV). The orthopoxviruses have evolved several mechanisms to subvert the IFN- response. IFN--binding protein (IFN-BP) is a virally encoded homologue of the host IFN- receptor that blocks the effects of IFN- in the infected host. Unlike the cellular receptors, whose ligand specificity is restricted to their own species, the orthopoxvirus IFN-BPs bind IFN- from several species. The reason for this relaxed specificity has yet to be explained. ECTV, a mouse pathogen, encodes an IFN-BP that has been shown to inhibit the activity of both human and murine IFN- (hIFN- and mIFN-, respectively). In contrast, the IFN-BP from VACV is unable to inhibit mIFN-, but retains activity against hIFN-. To determine which region(s) in the ECTV sequence is responsible for its ability to bind to mIFN- with high affinity, a series of chimeric IFN-BPs, as well as individual point mutants in the ECTV sequence corresponding to the amino acid changes from the VACV sequence, were constructed. The affinities of the chimeric and point mutant IFN-BPs for mIFN- were tested by using surface plasmon resonance and bioassay. By using this strategy, several key residues in the ligand-binding domains of the ECTV sequence have been identified that are responsible for high-affinity binding to mIFN-. Substitution of the ECTV residue at these positions in VACV resulted in a dramatic increase in the affinity of the VACV IFN-BP for mIFN-.

Supplementary figures showing covalent dimerization of IFN-BP constructs and gel-filtration analysis of IFN-BP point mutants are available in JGV Online.

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				A. A. Nuara, L. J. Walter, N. J. Logsdon, S. I. Yoon, B. C. Jones, J. M. Schriewer, R. M. Buller, and M. R. Walter Structure and mechanism of IFN-{gamma} antagonism by an orthopoxvirus IFN-{gamma}-binding protein PNAS, February 12, 2008; 105(6): 1861 - 1866. [Abstract] [Full Text] [PDF]