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Journal of Virology, November 2006, p. 10675-10682, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01015-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Unique C Termini of Orthopoxvirus Gamma Interferon Binding Proteins Are Essential for Ligand Binding{triangledown} ,{dagger}

Anthony A. Nuara,1 Hongdong Bai,2 Nanhai Chen,3 R. Mark L. Buller,1* and Mark R. Walter4

Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, St. Louis, Missouri 63104,1 Department of Cell Biology, Division of Vascular Biology, Scripps Research Institute, La Jolla, California 92037,2 Genelux Corporation, San Diego, California 92109,3 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 352054

Received 17 May 2006/ Accepted 9 August 2006

The orthopoxviruses ectromelia virus (ECTV) and vaccinia virus (VACV) express secreted gamma interferon binding proteins (IFN-{gamma}BPs) with homology to the ligand binding domains of the host's IFN-{gamma} receptor (IFN-{gamma}R1). Homology between these proteins is limited to the extracellular portions of the IFN-{gamma}R1 and the first ~200 amino acids of the IFN-{gamma}BPs. The remaining 60 amino acids at the C termini of the IFN-{gamma}BPs contain a single cysteine residue shown to be important in covalent dimerization of the secreted proteins. The function of the remaining C-terminal domain (CTD) has remained elusive, yet this region is conserved within all orthopoxvirus IFN-{gamma}BPs. Using a series of C-terminal deletion constructs, we have determined that the CTD is essential for IFN-{gamma} binding despite having no predicted homology to the IFN-{gamma}R1. Truncation of the ECTV IFN-{gamma}BP by more than two amino acid residues results in a complete loss of binding activity for both murine IFN-{gamma} and human IFN-{gamma} (hIFN-{gamma}), as measured by surface plasmon resonance (SPR) and bioassay. Equivalent truncation of the VACV IFN-{gamma}BP resulted in comparable loss of hIFN-{gamma} binding activity by SPR. Full-length IFN-{gamma}BPs were observed to form higher-ordered structures larger than the previously reported dimers. Mutants that were unable to bind IFN-{gamma} with high affinity in SPR experiments failed to assemble into these higher-ordered structures and migrated as dimers. We conclude that the unique CTD of orthopoxvirus IFN-{gamma}BPs is important for the assembly of covalent homodimers as well as the assembly of higher-ordered structures essential for IFN-{gamma} binding.

* Corresponding author. Mailing address: Saint Louis University, Department of Molecular Microbiology and Immunology, 1402 South Grand Blvd., St. Louis, MO 63104. Phone: (314) 977-8870. Fax: (314) 977-8717. E-mail: bullerrm{at}slu.edu.

{triangledown} Published ahead of print on 23 August 2006.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, November 2006, p. 10675-10682, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.01015-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nuara, A. A., Walter, L. J., Logsdon, N. J., Yoon, S. I., Jones, B. C., Schriewer, J. M., Buller, R. M., Walter, M. R. (2008). Structure and mechanism of IFN-{gamma} antagonism by an orthopoxvirus IFN-{gamma}-binding protein. Proc. Natl. Acad. Sci. USA 105: 1861-1866 [Abstract] [Full Text]  
  • Sakala, I. G., Chaudhri, G., Buller, R. M., Nuara, A. A., Bai, H., Chen, N., Karupiah, G. (2007). Poxvirus-Encoded Gamma Interferon Binding Protein Dampens the Host Immune Response to Infection. J. Virol. 81: 3346-3353 [Abstract] [Full Text]  


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