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Journal of Virology, April 2008, p. 3283-3294, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01935-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification of Hot Spots in the Variola Virus Complement Inhibitor (SPICE) for Human Complement Regulation{triangledown}

Viveka Nand Yadav, Kalyani Pyaram, Jayati Mullick, and Arvind Sahu*

National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, India

Received 4 September 2007/ Accepted 2 January 2008

Variola virus, the causative agent of smallpox, encodes a soluble complement regulator named SPICE. Previously, SPICE has been shown to be much more potent in inactivating human complement than the vaccinia virus complement control protein (VCP), although they differ only in 11 amino acid residues. In the present study, we have expressed SPICE, VCP, and mutants of VCP by substituting each or more of the 11 non-variant VCP residues with the corresponding residue of SPICE to identify hot spots that impart functional advantage to SPICE over VCP. Our data indicate that (i) SPICE is ~90-fold more potent than VCP in inactivating human C3b, and the residues Y98, Y103, K108 and K120 are predominantly responsible for its enhanced activity; (ii) SPICE is 5.4-fold more potent in inactivating human C4b, and residues Y98, Y103, K108, K120 and L193 mainly dictate this increase; (iii) the classical pathway decay-accelerating activity of activity is only twofold higher than that of VCP, and the 11 mutations in SPICE do not significantly affect this activity; (iv) SPICE possesses significantly greater binding ability to human C3b compared to VCP, although its binding to human C4b is lower than that of VCP; (v) residue N144 is largely responsible for the increased binding of SPICE to human C3b; and (vi) the human specificity of SPICE is dictated primarily by residues Y98, Y103, K108, and K120 since these are enough to formulate VCP as potent as SPICE. Together, these results suggest that principally 4 of the 11 residues that differ between SPICE and VCP partake in its enhanced function against human complement.

* Corresponding author. Mailing address: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007, India. Phone: 91-20-2570-8083. Fax: 91-20-2569-2259. E-mail: arvindsahu{at}nccs.res.in

{triangledown} Published ahead of print on 23 January 2008.

Journal of Virology, April 2008, p. 3283-3294, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01935-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Singh, A. K., Yadav, V. N., Pyaram, K., Mullick, J., Sahu, A. (2009). Mapping of Functional Domains in Herpesvirus Saimiri Complement Control Protein Homolog: Complement Control Protein Domain 2 Is the Smallest Structural Unit Displaying Cofactor and Decay-Accelerating Activities. J. Virol. 83: 10299-10304 [Abstract] [Full Text]  
  • Liszewski, M. K., Leung, M. K., Hauhart, R., Fang, C. J., Bertram, P., Atkinson, J. P. (2009). Smallpox Inhibitor of Complement Enzymes (SPICE): Dissecting Functional Sites and Abrogating Activity. J. Immunol. 183: 3150-3159 [Abstract] [Full Text]  
  • Thorgersen, E. B., Pharo, A., Haverson, K., Axelsen, A. K., Gaustad, P., Kotwal, G. J., Sfyroera, G., Mollnes, T. E. (2009). Inhibition of Complement and CD14 Attenuates the Escherichia coli-Induced Inflammatory Response in Porcine Whole Blood. Infect. Immun. 77: 725-732 [Abstract] [Full Text]  
  • Liszewski, M. K., Bertram, P., Leung, M. K., Hauhart, R., Zhang, L., Atkinson, J. P. (2008). Smallpox Inhibitor of Complement Enzymes (SPICE): Regulation of Complement Activation on Cells and Mechanism of Its Cellular Attachment. J. Immunol. 181: 4199-4207 [Abstract] [Full Text]  


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