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J. Biol. Chem., Vol. 279, Issue 43, 45093-45101, October 22, 2004

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The Kaposi's Sarcoma-associated Herpesvirus Complement Control Protein Mimics Human Molecular Mechanisms for Inhibition of the Complement System^*

Linda Mark, Wen H. Lee¶, O. Brad Spiller||**, David Proctor||, David J. Blackbourn**, Bruno O. Villoutreix¶, and Anna M. Blom

From the Department of Clinical Chemistry, Lund University, University Hospital Malmö, S-20502 Malmö, Sweden, INSERM U428, University of Paris V, Paris 75006, France, the ^||University of Wales College of Medicine, Virus receptor and Immune Evasion Group, Department of Medical Biochemistry, Heath Park, Cardiff CF14 4XX, United Kingdom, and the Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Church Street, Glasgow G11 5JR, United Kingdom

Kaposi's sarcoma-associated human herpesvirus (KSHV) is thought to cause Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Previously, we reported that the KSHV complement control protein (KCP) encoded within the viral genome is a potent regulator of the complement system; it acts both as a cofactor for factor I and accelerates decay of the C3 convertases (Spiller, O. B., Blackbourn, D. J., Mark, L., Proctor, D. G., and Blom, A. M. (2003) J. Biol. Chem. 278, 9283-9289). KCP is a homologue to human complement regulators, being comprised of four complement control protein (CCP) domains. In this, the first study to identify the functional sites of a viral homologue at the amino acid level, we created a three-dimensional homology-based model followed by site-directed mutagenesis to locate complement regulatory sites. Classical pathway regulation, both through decay acceleration and factor I cleavage of C4b, required a cluster of positively charged amino acids in CCP1 stretching into CCP2 (Arg-20, Arg-33, Arg-35, Lys-64, Lys-65, and Lys-88) as well as positively (Lys-131, Lys-133, and His-135) and negatively (Glu-99, Glu-152, and Asp-155) charged areas at opposing faces of the border region between CCPs 2 and 3. The regulation of the alternative pathway (via factor I-mediated C3b cleavage) was found to both overlap with classical pathway regulatory sites (Lys-64, Lys-65, Lys-88 and Lys-131, Lys-133, His-135) as well as require unique, more C-terminal residues in CCPs 3 and 4 (His-158, His-171, and His-213) and CCP 4 (Phe-195, Phe-207, and Leu-209). We show here that KCP has evolved to maintain the spatial structure of its functional sites, especially the positively charged patches, compared with host complement regulators.

Received for publication, July 7, 2004

^* This study was supported by grants from the Cancerfonden, Swedish Research Council, Foundations of österlund, Kock, Crafoord, Groschinsky, Hain, Zoega, Svartz, Bergvalls, and Påhlsson, the Royal Physiographic Society in Lund, the King Gustav V 80th Anniversary Foundation, and the American Cancer Foundation as well as research grants from the University Hospital in Malmö. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by the INSERM Institute and la region Ile de France.

^** Supported by Cancer Research UK Grant C7934.

To whom correspondence should be addressed: U-MAS, Wallenberg Laboratory, Entrance 46, 6th Floor, S-20502 Malmö, Sweden. Tel.: 46-40-338233; Fax: 46-40-337044; E-mail: anna.blom{at}klkemi.mas.lu.se.

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