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J. Biol. Chem., Vol. 283, Issue 32, 22113-22120, August 8, 2008

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Structure-Function Analysis of the C3 Binding Region of Staphylococcus aureus Immune Subversion Protein Sbi^*

Abhishek Upadhyay, Julia D. Burman, Elizabeth A. Clark¹, Elisa Leung, David E. Isenman, Jean M. H. van den Elsen², and Stefan Bagby³

From the Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom and the Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Among the recently discovered Staphylococcus aureus immune evasion proteins, Sbi is unique in its ability to interact with components of both the adaptive and innate immune systems of the host. Sbi domains I and II (Sbi-I and Sbi-II) bind IgG. Sbi domain IV (residues 198–266) binds the central complement protein C3. When linked to Sbi-III, Sbi-IV induces a futile consumption of complement via alternative pathway activation, whereas isolated Sbi-IV specifically inhibits the alternative pathway without complement consumption. Here we have determined the three-dimensional structure of Sbi-IV by NMR spectroscopy, showing that Sbi-IV adopts a three-helix bundle fold similar to those of the S. aureus complement inhibitors Efb-C, Ehp, and SCIN. The ¹H-¹⁵N HSQC spectrum of Sbi-III indicates that this domain, essential for futile complement consumption, is natively unfolded, at least when isolated from the rest of Sbi. Sbi-IV and Sbi-III-IV both bind C3dg with 1:1 stoichiometry and submicromolar affinity. Despite low overall sequence identity, Sbi possesses the same residues as Efb at two positions essential for Efb-C binding to C3d. Mutation to alanine of either of these residues, Arg-231 and Asn-238, abolishes both Sbi-IV binding to C3dg and Sbi-IV alternative pathway inhibition. The almost complete conservation of Sbi-III and Sbi-IV amino acid sequences across more than 30 strains isolated from human and animal hosts indicates that the unique mechanism of Sbi in complement system subversion is a feature of infections of both humans and economically important animals.

Received for publication, April 4, 2008 , and in revised form, May 19, 2008.

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

^* This work was supported by Wellcome Trust Grant 076124 (to S. B.), Biotechnology and Biological Sciences Research Council Research Grant BBS/B/12121 (to J. M. H. v. d. E.), and Canadian Institutes of Health Research Grant MOP-7081 (to D. E. I.). 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.

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The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Supported by a BBSRC Ph.D. studentship.

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² To whom correspondence may be addressed. Tel.: 44-0-1225-383639; Fax: 44-0-1225-386779; E-mail: bssjmhve{at}bath.ac.uk. ³ To whom correspondence may be addressed. Tel.: 44-0-1225-386436; Fax: 44-0-1225-386779; E-mail: bsssb{at}bath.ac.uk.

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