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J. Biol. Chem., Vol. 281, Issue 22, 15464-15474, June 2, 2006

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Streptococcus pneumoniae Recruits Complement Factor H through the Amino Terminus of CbpA^*

From the Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208

Streptococcus pneumoniae, a human pathogen, is naturally capable of colonizing the upper airway and sometimes disseminating to remote tissue sites. Previous studies have shown that S. pneumoniae is able to evade complement-mediated innate immunity by recruiting complement factor H (FH), a complement alternative pathway inhibitor. Pneumococcal binding to FH has been attributed to choline-binding protein A (CbpA) of S. pneumoniae and its allelic variants, all of which are surface-exposed proteins. In this study, we sought to determine the molecular basis of the CbpA-FH binding interaction. Initial deletional analysis of the CbpA protein in strain D39 (capsular serotype 2) revealed that the N-terminal region of 89 amino acids in the mature CbpA protein is required for FH binding. Immunofluorescence microscopy analysis showed that this region of CbpA is also necessary for FH deposition to the surface of the intact pneumococci. Moreover, recombinant proteins representing the 104 amino acids of the N-terminal CbpA alone was sufficient for high affinity binding to FH (K_D < 1 nM). The FH binding activity was finally localized to a 12-amino acid motif in the N-terminal CbpA by peptide mapping. Further kinetic analysis suggested that additional amino acids downstream of the 12-amino acid motif provide necessary structural or conformational support for the CbpA-FH interaction. The 12-amino acid motif and its adjacent regions contain highly conserved residues among various CbpA alleles, suggesting that this region may mediate FH binding in multiple pneumococcal strains.

Received for publication, March 14, 2006 , and in revised form, March 30, 2006.

^* This work was supported in part by American Lung Association Grant RG-178-N and National Institutes of Health Grants AI054753 and DC006917. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ To whom correspondence should be addressed: Center for Immunology and Microbial Disease, Albany Medical College, M/C 151, Rm. MS453, 47 New Scotland Ave., Albany, NY 12208. Tel.: 518-262-6412; Fax: 518-262-6161; E-mail: zhangj{at}mail.amc.edu.

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