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J. Biol. Chem., Vol. 280, Issue 26, 25095-25102, July 1, 2005

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Analysis of Binding Sites in Human C-reactive Protein for FcRI, FcRIIA, and C1q by Site-directed Mutagenesis^*

Ranhy Bang, Lorraine Marnell, Carolyn Mold¶, Mary-Pat Stein¶, Kevin T. Du Clos, Corinn Chivington-Buck, and Terry W. Du Clos||

From the Department of Veterans Affairs Medical Center and the University of New Mexico, School of Medicine, Departments of ^¶Molecular Genetics and Microbiology and Internal Medicine, Albuquerque, New Mexico 87108

Human C-reactive protein (CRP) is a classical, acute phase serum protein synthesized by the liver in response to infection, inflammation, or trauma. CRP binds to microbial antigens and damaged cells, opsonizes particles for phagocytosis and regulates the inflammatory response by the induction of cytokine synthesis. These activities of CRP depend on its ability to activate complement and to bind to Fc receptors (FcR). The goal of this study was to elucidate amino acid residues important for the interaction of CRP with human FcRI (CD64) and FcRIIa (CD32). Several mutations of the CRP structure were studied based on the published crystal structure of CRP. Mutant and wild-type recombinant CRP molecules were expressed in the baculovirus system and their interactions with FcR and C1q were determined. A previous study by our laboratory identified an amino acid position, Leu¹⁷⁶, critical for CRP binding to FcRI and work by others (Agrawal, A., Shrive, A. K., Greenhough, T. J., and Volanakis, J. E. (2001) J. Immunol. 166, 3998-4004) determined several residues important for C1q binding. The amino acid residues important to CRP binding to FcRIIa were previously unknown. This study newly identifies residues Thr¹⁷³ and Asn¹⁸⁶ as important for the binding of CRP to FcRIIa and FcRI. Lys¹¹⁴, like Leu¹⁷⁶, was implicated in binding to FcRI, but not FcRIIa. Single mutations at amino acid positions Lys¹¹⁴, Asp¹⁶⁹, Thr¹⁷³, Tyr¹⁷⁵, and Leu¹⁷⁶ affected C1q binding to CRP. These results further identify amino acids involved in the binding sites on CRP for FcRI, FcRIIa, and C1q and indicate that these sites are overlapping.

Received for publication, May 2, 2005

^* This work was supported by the Department of Veterans Affairs and National Institutes of Health Grant AI 28358. 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.

^|| To whom correspondence should be addressed: VA Medical Center, Research Service 151, 1501 San Pedro SE, Albuquerque, NM 87108. Tel.: 505-256-5717; Fax: 505-256-2794; E-mail: tduclos{at}unm.edu.

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