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Structural basis for sialic acid–mediated self-recognition by complement factor H

Nature Chemical Biology volume 11, pages 77–82 (2015)Cite this article

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Abstract

The serum protein complement factor H (FH) ensures downregulation of the complement alternative pathway, a branch of innate immunity, upon interaction with specific glycans on host cell surfaces. Using ligand-based NMR, we screened a comprehensive set of sialylated glycans for binding to FH and solved the crystal structure of a ternary complex formed by the two C-terminal domains of FH, a sialylated trisaccharide and the complement C3b thioester–containing domain. Key residues in the sialic acid binding site are conserved from mice to men, and residues linked to atypical hemolytic uremic syndrome cluster within this binding site, suggesting a possible role for sialic acid as a host marker also in other mammals and a critical role in human renal complement homeostasis. Unexpectedly, the FH sialic acid binding site is structurally homologous to the binding sites of two evolutionarily unrelated proteins. The crystal structure also advances our understanding of bacterial immune evasion strategies.

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Figure 1: Chemical formulas of glycans tested in the STD NMR experiments with full-length FH.
Figure 2: FH binds α2-3 linked sialic acid glycans in its C-terminal domain.
Figure 3: The sialic acid FH binding site is a hot spot for aHUS mutations.
Figure 4: Orientation of the ternary host recognition complex on cellular surfaces.

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Acknowledgements

The authors thank R. Sprangers (Max Planck Institute for Development Biology, Tübingen, Germany), for assistance with NMR spectra collection, the SLS beamline staff (Paul Scherrer Institute, Villigen, Switzerland) for assistance with crystallographic data collection and H. Hengel (University Hospital Tübingen) for performing venipuncture and assistance with serum preparation. Funding was provided by the University of Tübingen Program for the Promotion of Junior Researchers and the University Hospital Tübingen Fortüne program (2186-0-0 to B.S.B.). D.K. is a Wellcome Trust intermediate clinical fellow.

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Authors and Affiliations

  1. Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany

    Bärbel S Blaum & Thilo Stehle

  2. Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA

    Jonathan P Hannan

  3. The School of Chemistry, University of Edinburgh, Scotland, UK

    Andrew P Herbert & Dušan Uhrín

  4. Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK

    David Kavanagh

  5. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Thilo Stehle

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  1. Bärbel S Blaum
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Contributions

B.S.B. designed, conducted and analyzed experiments. J.P.H. advised crystallization, and D.U. advised NMR experiments. J.P.H., A.P.H., D.K. and D.U. provided proteins. D.U. provided glycans. T.S. supervised the project and provided vital reagents. All authors discussed findings. B.S.B. and T.S. wrote the manuscript.

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Correspondence to Bärbel S Blaum.

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Blaum, B., Hannan, J., Herbert, A. et al. Structural basis for sialic acid–mediated self-recognition by complement factor H. Nat Chem Biol 11, 77–82 (2015). https://doi.org/10.1038/nchembio.1696

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