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Structure of complement fragment C3b–factor H and implications for host protection by complement regulators

Nature Immunology volume 10, pages 728–733 (2009)Cite this article

Abstract

Factor H (FH) is an abundant regulator of complement activation and protects host cells from self-attack by complement. Here we provide insight into the regulatory activity of FH by solving the crystal structure of the first four domains of FH in complex with its target, complement fragment C3b. FH interacted with multiple domains of C3b, covering a large, extended surface area. The structure indicated that FH destabilizes the C3 convertase by competition and electrostatic repulsion and that FH enables proteolytic degradation of C3b by providing a binding platform for protease factor I while stabilizing the overall domain arrangement of C3b. Our results offer general models for complement regulation and provide structural explanations for disease-related mutations in the genes encoding both FH and C3b.

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Figure 1: Characterization of recombinant FH(1–4).
Figure 2: Structure of C3b in complex with FH(1–4).
Figure 3: Mapping of FH and C3 mutants on the complex structure.
Figure 4: Structural basis of decay-acceleration activity.
Figure 5: Structural implications of cofactor activity.

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Acknowledgements

We thank the European Synchrotron Radiation Facility for synchrotron radiation facilities; beamline scientists of the European Synchrotron Radiation Facility and the European Molecular Biology Laboratory for assistance; M. Pangburn (University of Texas at Tyler) for the CFH clone; P. Barlow (University of Edinburgh) for FH(19–20) protein; and M.A. Hadders for critical reading of the manuscript and comments. Supported by the Council for Chemical Sciences of the Netherlands Organization for Scientific Research (P.G.) and the US National Institutes of Health (J.D.L.).

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Author notes

  1. John D Lambris and Piet Gros: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, The Netherlands

    Jin Wu, Bert J C Janssen & Piet Gros

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

    You-Qiang Wu, Daniel Ricklin & John D Lambris

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  1. Jin Wu
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  4. Bert J C Janssen
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  5. John D Lambris
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Contributions

J.W. purified C3 and C3b; Y.-Q.W. expressed and purified FH(1–4) and did cofactor assays; D.R. did decay acceleration, antibody competition and direct binding studies; J.W. crystallized the complex, collected data and determined, refined and analyzed the structure; B.J.C.J. helped with all stages of structure determination and analysis; J.D.L. and P.G. conceived and supervised the project; and J.W., D.R. and P.G. wrote the manuscript.

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Correspondence to John D Lambris or Piet Gros.

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Supplementary Figures 1–9, Tables 1–2 and Supplementary Methods (PDF 4779 kb)

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Wu, J., Wu, YQ., Ricklin, D. et al. Structure of complement fragment C3b–factor H and implications for host protection by complement regulators. Nat Immunol 10, 728–733 (2009). https://doi.org/10.1038/ni.1755

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