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J. Biol. Chem., Vol. 281, Issue 6, 3690-3697, February 10, 2006

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Human C4b-binding Protein, Structural Basis for Interaction with Streptococcal M Protein, a Major Bacterial Virulence Factor^*

Huw T. Jenkins, Linda Mark, Graeme Ball, Jenny Persson^¶, Gunnar Lindahl^¶, Dusan Uhrin, Anna M. Blom, and Paul N. Barlow¹

From the Edinburgh Biological NMR Unit, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, Scotland, United Kingdom, the Department of Laboratory Medicine, Section of Clinical Chemistry, University Hospital Malmö, Lund University, S-20502 Malmö, Sweden, and the ^¶Department of Laboratory Medicine, Division of Medical Microbiology, Lund University, Sölvegatan 23, SE-22362 Lund, Sweden

Human C4b-binding protein (C4BP) protects host tissue, and those pathogens able to hijack this plasma glycoprotein, from complement-mediated destruction. We now show that the first two complement control protein (CCP) modules of the C4BP -chain, plus the four residues connecting them, are necessary and sufficient for binding a bacterial virulence factor, the Streptococcus pyogenes M4 (Arp4) protein. Structure determination by NMR reveals two tightly coupled CCP modules in an elongated arrangement within this region of C4BP. Chemical shift perturbation studies demonstrate that the N-terminal, hypervariable region of M4 binds to a site including strand 1 of CCP module 2. This interaction is accompanied by an intermodular reorientation within C4BP. We thus provide a detailed picture of an interaction whereby a pathogen evades complement.

Received for publication, October 25, 2005 , and in revised form, November 30, 2005.

The atomic coordinates and structure factors (code 2A55) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The chemical shift assignments for C4BP12 have been deposited at the BioMagResBank under accession number 6712.

^* This work was supported by the Swedish Research Council (to A. M. B. and G. L.), the Swedish Foundation for Strategic Research (INGVAR) (to A. M. B.), the Medical Research Council of the United Kingdom (to P. N. B. and H. T. J.), and the Wellcome Trust. 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.

¹ To whom correspondence should be addressed: Schools of Chemistry and Biological Sciences, Joseph Black Chemistry Bldg., University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, Scotland, UK. Tel.: 44-131-650-4727; Fax: 44-131-650-7055; E-mail, Paul.Barlow{at}ed.ac.uk.

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