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* Medical Microbiology, University Medical Center Utrecht, The Netherlands; and
Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, The Netherlands
The pathogenic bacterium Staphylococcus aureus counteracts the host immune defense by excretion of the 85 residue staphylococcal complement inhibitor (SCIN). SCIN inhibits the central complement convertases; thereby, it reduces phagocytosis following opsonization and efficiently blocks all downstream effector functions. In this study, we present the crystal structure of SCIN at 1.8 Å resolution and the identification of its active site. Functional characterization of structure based chimeric proteins, consisting of SCIN and the structurally but nonfunctional homologue open reading frame-D, indicate an 18-residue segment (Leu-31—Gly-48) crucial for SCIN activity. In all complement activation pathways, chimeras lacking these SCIN residues completely fail to inhibit production of the potent mediator of inflammation C5a. Inhibition of alternative pathway-mediated opsonization (C3b deposition) and formation of the lytic membrane attack complex (C5b-9 deposition) are strongly reduced for these chimeras as well. For inhibition of the classical/lectin pathway-mediated C3b and C5b-9 deposition, the same residues are critical although additional sites are involved. These chimeras also display reduced capacity to stabilize the C3 convertases of both the alternative and the classical/lectin pathway indicating the stabilizing effect is pivotal for the complement inhibitory activity of SCIN. Because SCIN specifically and efficiently inhibits complement, it has a high potential in anti-inflammatory therapy. Our data are a first step toward the development of a second generation molecule suitable for such therapeutic complement intervention.
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1 This work was supported by grants from: Netherlands Organization for Scientific Research-VENI (916-76-037), a "Pionier" Programme Grant (to P.G.) of the Council for Chemical Sciences of Netherlands Organization for Scientific Research and Netherlands Genomics Initiative-Horizon (050-71-028).
2 S.H.M.R. and F.J.M. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Suzan H. M. Rooijakkers, Medical Microbiology, University Medical Center Utrecht, Room G04.614, Heidelberglaan 100, Utrecht, The Netherlands. E-mail address: s.h.m.rooijakkers{at}umcutrecht.nl
4 Abbreviations used in this paper: CP, classical pathway; LP, lectin pathway; AP, alternative pathway; SSL, staphylococcal superantigen like; CHIPS, chemotaxis inhibitory protein of S. aureus; Efb, extracellular fibrinogen-binding protein; SCIN, staphylococcal complement inhibitor; MAD, multiwavelength anomalous dispersion; His, histidine; RCA, regulators of complement activation; Efb-C, C3-binding domain of Efb.
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