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A structural basis for complement inhibition by Staphylococcus aureus

Nature Immunology volume 8, pages 430–437 (2007)Cite this article

Abstract

To provide insight into bacterial suppression of complement-mediated immunity, we present here structures of a bacterial complement inhibitory protein, both free and bound to its complement target. The 1.25-Å structure of the complement component C3–inhibitory domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb-C) demonstrated a helical motif involved in complement regulation, whereas the 2.2-Å structure of Efb-C bound to the C3d domain of human C3 allowed insight into the recognition of complement proteins by invading pathogens. Our structure-function studies provided evidence for a previously unrecognized mode of complement inhibition whereby Efb-C binds to native C3 and alters the solution conformation of C3 in a way that renders it unable to participate in successful 'downstream' activation of the complement response.

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Figure 1: Crystal structure of Efb-C at 1.25 Å.
Figure 2: Crystal structure of the Efb-C–C3d complex at 2.2 Å.
Figure 3: Inhibition of C3 activation requires binding of Efb to the C3d domain.
Figure 4: Structural basis of complement inhibition by Efb-C.
Figure 5: Efb-C binds to native forms of C3.
Figure 6: Proposed structural basis for the differential recognition of C3 fragments by Efb-C.

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Acknowledgements

We thank Z. Jin and J. Chrzas of SER-CAT beamlines 22-ID and 22-BM from the Advanced Photon Source of Argonne National Laboratory for technical assistance with diffraction data collection; A. Rux and B. Sachais (University of Pennsylvania) for support with the Biacore 2000; and D. Leahy, S. Bouyain and K. Ramyar for comments during the preparation of this manuscript. C3-9 was provided by C. Erik Hack (Central Laboratory of The Netherlands Red Cross Blood Transfusion Service). Supported by the School of Biological Sciences at the University of Missouri-Kansas City, the University of Missouri Research Board (2509 to B.V.G.) and the National Institute of Allergy and Infectious Diseases (AI30040 to J.D.L.).

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Author notes

  1. Michal Hammel

    Present address: Present address: Advanced Light Source, Lawrence Berkeley Laboratory, Berkeley, California 94720, USA.,

  2. Michal Hammel and Georgia Sfyroera: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri at Kansas City, Kansas City, 64110, Missouri, USA

    Michal Hammel & Brian V Geisbrecht

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Georgia Sfyroera, Daniel Ricklin, Paola Magotti & John D Lambris

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Contributions

M.H. and B.V.G., structural biology and titration calorimetry; G.S., D.R., P.M. and J.D.L., functional assays and SPR.

Corresponding author

Correspondence to Brian V Geisbrecht.

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Competing interests

Michal Hammel, Georgia Sfyroera, Daniel Ricklin, Paola Magotti, John D Lambris & Brian V Geisbrecht B.V.G. and J.D.L. have applied for a provisional patent concerning potential therapeutic applications of the complexes described.

Supplementary information

Supplementary Fig. 1

Structural comparisons between Efb-C and a protein A module from S. aureus. (PDF 123 kb)

Supplementary Fig. 2

Spatial relationship of Efb-C to the conserved acidic groove of C3d as seen in the Efb-C–C3d crystal structure. (PDF 711 kb)

Supplementary Fig. 3

Structural integrity of the Efb-C-(RENE) mutant. (PDF 595 kb)

Supplementary Fig. 4

Efb-binding renders C3 susceptible to proteolysis in vitro. (PDF 56 kb)

Supplementary Fig. 5

Degradation of C3 in complement-inactivated plasma in the presence of Efb-C. (PDF 181 kb)

Supplementary Fig. 6

Alternative depiction of structural models for Efb-C bound to C3 and C3b. (PDF 417 kb)

Supplementary Methods (PDF 182 kb)

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Hammel, M., Sfyroera, G., Ricklin, D. et al. A structural basis for complement inhibition by Staphylococcus aureus. Nat Immunol 8, 430–437 (2007). https://doi.org/10.1038/ni1450

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