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Pathogenic bacteria attach to human fibronectin through a tandem β-zipper

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Abstract

Staphylococcus aureus and Streptococcus pyogenes, two important human pathogens, target host fibronectin (Fn) in their adhesion to and invasion of host cells1,2. Fibronectin-binding proteins (FnBPs), anchored in the bacterial cell wall, have multiple Fn-binding repeats3 in an unfolded4,5 region of the protein. The bacterium-binding site in the amino-terminal domain (1–5F1) of Fn contains five sequential Fn type 1 (F1) modules. Here we show the structure of a streptococcal (S. dysgalactiae) FnBP peptide (B3)6,7 in complex with the module pair 1F12F1. This identifies 1F1- and 2F1-binding motifs in B3 that form additional antiparallel β-strands on sequential F1 modules—the first example of a tandem β-zipper. Sequence analyses of larger regions of FnBPs from S. pyogenes and S. aureus reveal a repeating pattern of F1-binding motifs that match the pattern of F1 modules in 1–5F1 of Fn. In the process of Fn-mediated invasion of host cells, therefore, the bacterial proteins seem to exploit the modular structure of Fn by forming extended tandem β-zippers. This work is a vital step forward in explaining the full mechanism of the integrin-dependent2,8 FnBP-mediated invasion of host cells.

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Figure 1: Family of NMR-derived structures of the 1F12F1 module pair from human Fn complexed with B3 from S. dysgalactiae (Table 1).
Figure 2: Molecular surface (prepared using GRASP) and ribbon diagram (prepared with MOLMOL) of 1F12F1–B3.
Figure 3: The extended tandem β-zipper model.

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Acknowledgements

We thank R. Aplin for mass spectrometry, M. Pitkeathly for peptide synthesis, and S. Lukomski for the S. pyogenes M75 DNA (4673). This research was supported by the Wellcome Trust and the Biotechnology and the Biological Sciences Research Council. J.R.P. acknowledges the British Heart Foundation for financial support.

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Author notes

  1. John A. G. Briggs

    Present address: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK

Authors and Affiliations

  1. Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU, Oxford, UK

    Ulrich Schwarz-Linek, Jörn M. Werner, Andrew R. Pickford, Ewa S. Pilka, John A. G. Briggs, T. Sebastian Gough, Iain D. Campbell & Jennifer R. Potts

  2. Center for Extracellular Matrix Biology, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas, 77030-3303, USA

    Sivashankarappa Gurusiddappa, Jung Hwa Kim & Magnus Höök

  3. Oxford Centre for Molecular Sciences, Central Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QH, Oxford, UK

    Iain D. Campbell

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  1. Ulrich Schwarz-Linek
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Correspondence to Jennifer R. Potts.

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Schwarz-Linek, U., Werner, J., Pickford, A. et al. Pathogenic bacteria attach to human fibronectin through a tandem β-zipper. Nature 423, 177–181 (2003). https://doi.org/10.1038/nature01589

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