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Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates

Nature volume 458, pages 890–893 (2009)Cite this article

Abstract

The complement system is an essential component of the innate and acquired immune system1, and consists of a series of proteolytic cascades that are initiated by the presence of microorganisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including complement factor H (fH; ref. 2), a 155 kDa protein composed of 20 domains (termed complement control protein repeats). Many pathogens have evolved the ability to avoid immune-killing by recruiting host complement regulators3 and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface4. Here we present the structure of a complement regulator in complex with its pathogen surface-protein ligand. This reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, fH. The structure also indicates the molecular basis of the host-specificity of the interaction between fH and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.

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Figure 1: The fHbp binding site requires both CCP6 of fH and requires the complete extracellular portion of fHbp.
Figure 2: Structure of fHbp and its complex with fH67.
Figure 3: Interference with fHbp binding of fH.

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Accession codes

Primary accessions

Protein Data Bank

Data deposits

Coordinates and X-ray data have been deposited in the Protein Data Bank under accession numbers 2w80 and 2w81.

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Acknowledgements

Thanks are due to G. Bricogne and the Global Phasing Consortium for access to a β version of autoSHARP and autoBUSTER, to the beamline staff of the European Synchrotron Radiation Source (particularly G. Leonard) and DIAMOND (UK), and to many members of the Laboratory of Molecular Biophysics, Oxford, and the Lea group for help with X-ray data collection. B.E.P. was funded by a Wellcome Trust studentship; P.R. and S.J. by Medical Research Council grants to S.M.L.; J.E.D. by a Wellcome Trust grant to SM.L.; and J.E.L. by an Engineering and Physical Sciences Research Grant to S.M.L. Work in C.M.T.’s laboratory is funded by the Wellcome Trust and the Medical Research Council. E.K. is an EMBO fellow.

Author Contributions B.E.P., J.E.D. and J.J.E.C. performed SPR experiments; B.E.P., J.J.E.C., J.E.L. and S.Q. expressed proteins and crystallized the complex; M.C.S., E.K. and Q.Z. performed all assays with Neisseria and expressed fHbp; S.J., P.R. and S.M.L. collected and analysed X ray data; S.M.L. phased the X-ray data and built/refined the models; and S.M.L. and C.M.T. designed the research and wrote the paper.

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Author notes

  1. Muriel C. Schneider

    Present address: Present address: Harvard Medical School, Boston, Massachusetts 02115, USA.,

  2. Muriel C. Schneider and Beverly E. Prosser: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Molecular Microbiology and Infection, Imperial College, London SW7 2AZ, UK

    Muriel C. Schneider, Elisabeth Kugelberg, Su Li, Qian Zhang & Christoph M. Tang

  2. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK ,

    Beverly E. Prosser, Joseph J. E. Caesar, Sadik Quoraishi, Janet E. Lovett, Janet E. Deane, Pietro Roversi, Steven Johnson & Susan M. Lea

  3. Department of Biochemistry, MRC Immunochemistry Unit, University of Oxford, South Parks Road, Oxford OX1 3QU, UK,

    Robert B. Sim

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Correspondence to Christoph M. Tang or Susan M. Lea.

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Schneider, M., Prosser, B., Caesar, J. et al. Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature 458, 890–893 (2009). https://doi.org/10.1038/nature07769

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