KSHV complement control protein mimics human molecular mechanisms for inhibition of the complement system.

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KSHV complement control protein mimics human molecular mechanisms for inhibition of the complement system. / Mark, Linda; Lee, Wen H.; Spiller, O. Brad; Proctor, David; Blackbourn, David J.; Villoutreix, Bruno O.; Blom, Anna.

In: Journal of Biological Chemistry, Vol. 279, No. 43, 2004, p. 45093-45101.

Research output: Contribution to journalArticle

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Mark, Linda ; Lee, Wen H. ; Spiller, O. Brad ; Proctor, David ; Blackbourn, David J. ; Villoutreix, Bruno O. ; Blom, Anna. / KSHV complement control protein mimics human molecular mechanisms for inhibition of the complement system. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 43. pp. 45093-45101.

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TY - JOUR

T1 - KSHV complement control protein mimics human molecular mechanisms for inhibition of the complement system.

AU - Mark, Linda

AU - Lee, Wen H.

AU - Spiller, O. Brad

AU - Proctor, David

AU - Blackbourn, David J.

AU - Villoutreix, Bruno O.

AU - Blom, Anna

PY - 2004

Y1 - 2004

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M407558200

DO - 10.1074/jbc.M407558200

M3 - Article

C2 - 15304516

VL - 279

SP - 45093

EP - 45101

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 43

ER -