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J. Biol. Chem., Vol. 283, Issue 25, 17579-17593, June 20, 2008

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Interaction of Human Complement with Sbi, a Staphylococcal Immunoglobulin-binding Protein

INDICATIONS OF A NOVEL MECHANISM OF COMPLEMENT EVASION BY STAPHYLOCOCCUS AUREUS^*

Julia D. Burman¹, Elisa Leung¹, Karen L. Atkins², Maghnus N. O'Seaghdha^¶, Lea Lango³, Pau Bernadó^||4, Stefan Bagby, Dmitri I. Svergun^||**, Timothy J. Foster^¶, David E. Isenman⁵, and Jean M. H. van den Elsen⁶

From the Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom, the Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada, the ^¶Microbiology Department, Moyne Institute of Preventive Medicine, Trinity College, Dublin 2, Ireland, ^||EMBL, Hamburg Outstation, Notkestrasse 85, D-22603 Hamburg, Germany, and ^**Institute of Crystallography, Russian Academy of Sciences, Leninsky Pr. 59, 117333 Moscow, Russia

Staphylococcal immunoglobulin-binding protein, Sbi, is a 436-residue protein produced by many strains of Staphylococcus aureus. It was previously characterized as being cell surface-associated and having binding capacity for human IgG and β₂-glycoprotein I. Here we show using small angle x-ray scattering that the proposed extracellular region of Sbi (Sbi-E) is an elongated molecule consisting of four globular domains, two immunoglobulin-binding domains (I and II) and two novel domains (III and IV). We further show that together domains III and IV (Sbi-III-IV), as well as domain IV on its own (Sbi-IV), bind complement component C3 via contacts involving both the C3dg fragment and the C3a anaphylatoxin domain. Preincubation of human serum with either Sbi-E or Sbi-III-IV is inhibitory to all complement pathways, whereas domain IV specifically inhibits the alternative pathway. Monitoring C3 activation in serum incubated with Sbi fragments reveals that Sbi-E and Sbi-III-IV both activate the alternative pathway, leading to consumption of C3. By contrast, inhibition of this pathway by Sbi-IV does not involve C3 consumption. The observation that Sbi-E activates the alternative pathway is counterintuitive to intact Sbi being cell wall-associated, as recruiting complement to the surface of S. aureus would be deleterious to the bacterium. Upon re-examination of this issue, we found that Sbi was not associated with the cell wall fraction, but rather was found in the growth medium, consistent with it being an excreted protein. As such, our data suggest that Sbi helps mediate bacterial evasion of complement via a novel mechanism, namely futile fluid-phase consumption.

Received for publication, January 10, 2008 , and in revised form, February 12, 2008.

^* This work was supported in part by Biotechnology and Biological Sciences Research Council Research Grant BBS/B/12121 (to J. M. H. v. d. E.), Canadian Institutes of Health Research Grant MOP-7081 (to D. E. I.), and Wellcome Trust grant 076124 (to S. B.). 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 Figs. S1-S4.

¹ Both authors contributed equally to this work.

² Supported by a Medical Research Council studentship.

³ Present address: Dept. of Microbiology, University College Cork, Cork, Ireland.

⁴ Present address: Institut de Recerca Biomèdica, Parc Científic de Barcelona, Josep Samitier, 1-5, 08028-Barcelona, Spain.

⁵ To whom correspondence may be addressed. E-mail: d.isenman{at}utoronto.ca.

⁶ To whom correspondence may be addressed. E-mail: bssjmhve{at}bath.ac.uk.

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