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J. Virol. doi:10.1128/JVI.01935-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification of hot spots in the variola virus complement inhibitor (SPICE) for human complement regulation

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

^* To whom correspondence should be addressed. Email: arvindsahu{at}nccs.res.in.

	Abstract

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 eleven amino acid residues. In the present study, we have expressed SPICE, VCP and mutants of VCP by substituting each or more of the eleven 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 about 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) it is 5.4-fold more potent in inactivating human C4b and residues Y98, Y103, K108, K120 and L193 mainly dictate this increase, iii) its classical pathway decay-accelerating activity is only 2-fold higher than VCP and the eleven mutations in SPICE do not significantly affect this activity, iv) it possesses significantly higher binding ability to human C3b compared to VCP, however, its binding to human C4b is lower than VCP, v) residue N144 is largely responsible for its increased binding to human C3b, vi) its human specificity is dictated primarily by residues Y98, Y103, K108 and K120 these are enough to formulate VCP as potent as SPICE. Together, these results suggest that principally four of the eleven residues that differ between SPICE and VCP partake in its enhanced function against human complement.

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• 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]