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Journal of Virology, June 2000, p. 5659-5666, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Conserved Surface-Exposed K/R-X-K/R Motifs and Net Positive Charge on Poxvirus Complement Control Proteins Serve as Putative Heparin Binding Sites and Contribute to Inhibition of Molecular Interactions with Human Endothelial Cells: a Novel Mechanism for Evasion of Host Defense

Scott A. Smith,1 Nick P. Mullin,2 John Parkinson,2 Sergei N. Shchelkunov,3 Alexei V. Totmenin,3 V. N. Loparev,4 Ratchapin Srisatjaluk,1 David N. Reynolds,1 Kristen L. Keeling,1 David E. Justus,1 Paul N. Barlow,2 and Girish J. Kotwal1,*

Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky1; The Edinburgh Center for Protein Technology, The University of Edinburgh, Edinburgh EH9 3JJ, United Kingdom2; Department of Molecular Biology of Genomes, State Research Center of Virology and Biotechnology, Koltsovo, Novosibirsk Region, 633159 Russia3; and Poxvirus Section, Viral Exanthems and Herpesvirus Branch, Division of Viral and Rickettsial Diseases, National Center for Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia4

Received 6 December 1999/Accepted 6 March 2000

Vaccinia virus complement control protein (VCP) has been shown to possess the ability to inhibit both classical and alternative complement pathway activation. The newly found ability of this protein to bind to heparin has been shown in previous studies to result in uptake by mast cells, possibly promoting tissue persistence. It has also been shown to reduce chemotactic migration of leukocytes by blocking chemokine binding. In addition, this study shows that VCP---through its ability to bind to glycosaminoglycans (heparin-like molecules) on the surface of human endothelial cells---is able to block antibody binding to surface major histocompatibility complex class I molecules. Since heparin binding is critical for many functions of this protein, we have attempted to characterize the molecular basis for this interaction. Segments of this protein, generated by genetic engineering of the DNA encoding VCP into the Pichia pastoris expression system, were used to localize the regions with heparin binding activity. These regions were then analyzed to more specifically define their properties for binding. It was found that the number of putative binding sites (K/R-X-K/R), the overall positive charge, and the percentage of positively charged amino acids within the protein were responsible for this interaction.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202. Phone: (502) 852-5359. Fax: (502) 852-7531. E-mail: gjkotw01{at}gwise.louisville.edu.

Journal of Virology, June 2000, p. 5659-5666, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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