Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 423, pages 177–181 (2003)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Peacock, S. J., Foster, T. J., Cameron, B. J. & Berendt, A. R. Bacterial fibronectin-binding proteins and endothelial cell surface fibronectin mediate adherence of Staphylococcus aureus to resting human endothelial cells. Microbiology 145, 3477–3486 (1999)

    Article  CAS  Google Scholar 

  2. Ozeri, V., Rosenshine, I., Mosher, D. F., Fässler, R. & Hanski, E. Roles of integrins and fibronectin in the entry of Streptococcus pyogenes into cells via protein F1. Mol. Microbiol. 30, 625–637 (1998)

    Article  CAS  Google Scholar 

  3. Patti, J. M., Allen, B. L., McGavin, M. J. & Höök, M. MSCRAMM-mediated adherence of microorganisms to host tissues. Annu. Rev. Microbiol. 48, 585–617 (1994)

    Article  CAS  Google Scholar 

  4. House-Pompeo, K., Xu, Y., Joh, D., Speziale, P. & Höök, M. Conformational changes in the fibronectin binding MSCRAMMs are induced by ligand binding. J. Biol. Chem. 271, 1379–1384 (1996)

    Article  CAS  Google Scholar 

  5. Penkett, C. J. et al. Structural and dynamical characterization of a biologically active unfolded fibronectin-binding protein from Staphylococcus aureus. Biochemistry 37, 17054–17067 (1998)

    Article  CAS  Google Scholar 

  6. McGavin, M. J. et al. Fibronectin receptors from Streptococcus dysgalactiae and Staphylococcus aureus—involvement of conserved residues in ligand binding. J. Biol. Chem. 268, 23946–23953 (1993)

    CAS  PubMed  Google Scholar 

  7. Joh, D., Speziale, P., Gurusiddappa, S., Manor, J. & Höök, M. Multiple specificities of the staphylococcal and streptococcal fibronectin-binding microbial surface components recognizing adhesive matrix molecules. Eur. J. Biochem. 258, 897–905 (1998)

    Article  CAS  Google Scholar 

  8. Sinha, B. et al. Fibronectin-binding protein acts as Staphylococcus aureus invasin via fibronectin bridging to integrin α5β1 . Cell. Microbiol. 1, 101–117 (1999)

    Article  CAS  Google Scholar 

  9. Knodler, L. A., Celli, J. & Finlay, B. B. Pathogenic trickery: Deception of host cell processes. Nature Rev. Mol. Cell Biol. 2, 578–588 (2001)

    Article  CAS  Google Scholar 

  10. Ing, M. B., Baddour, L. M. & Bayers, S. A. in The Staphylococci in Human Disease (eds Crossley, K. B. & Archer, G. L.) 331–354 (Churchill Livingstone, New York, 1997)

    Google Scholar 

  11. Greene, C. et al. Adhesion properties of mutants of Staphylococcus aureus defective in fibronectin-binding proteins and studies on the expression of fnb genes. Mol. Microbiol. 17, 1143–1152 (1995)

    Article  CAS  Google Scholar 

  12. Potts, J. R., Bright, J. R., Bolton, D., Pickford, A. R. & Campbell, I. D. Solution structure of the N-terminal F1 module pair from human fibronectin. Biochemistry 38, 8304–8312 (1999)

    Article  CAS  Google Scholar 

  13. Jaffe, J., Natanson-Yaron, S., Caparon, M. G. & Hanski, E. Protein F2, a novel fibronectin-binding protein from Streptococcus pyogenes, possesses two binding domains. Mol. Microbiol. 21, 373–384 (1996)

    Article  CAS  Google Scholar 

  14. Penkett, C. J. et al. Identification of residues involved in the interaction of Staphylococcus aureus fibronectin-binding protein with the 4F15F1 module pair of human fibronectin using heteronuclear NMR spectroscopy. Biochemistry 39, 2887–2893 (2000)

    Article  CAS  Google Scholar 

  15. Talay, S. R., Valentin-Weigand, P., Jerlstrom, P. G., Timmis, K. N. & Chhatwal, G. S. Fibronectin-binding protein of Streptococcus pyogenes—sequence of the binding domain involved in adherence of streptococci to epithelial cells. Infect. Immun. 60, 3837–3844 (1992)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Signäs, C. et al. Nucleotide sequence of the gene for a fibronectin-binding protein from Staphylococcus aureus—use of this peptide sequence in the synthesis of biologically-active peptides. Proc. Natl Acad. Sci. USA 86, 699–703 (1989)

    Article  ADS  Google Scholar 

  17. Schwarz-Linek, U. et al. Binding of a peptide from a Streptococcus dysgalactiae MSCRAMM to the N-terminal F1 module pair of human fibronectin involves both modules. FEBS Lett. 497, 137–140 (2001)

    Article  CAS  Google Scholar 

  18. Huff, S., Matsuka, Y. V., McGavin, M. J. & Ingham, K. C. Interaction of N-terminal fragments of fibronectin with synthetic and recombinant D motifs from its binding protein on Staphylococcus aureus studied using fluorescence anisotropy. J. Biol. Chem. 269, 15563–15570 (1994)

    CAS  PubMed  Google Scholar 

  19. Massey, R. C. et al. Fibronectin-binding protein A of Staphylococcus aureus has multiple, substituting, binding regions that mediate adherence to fibronectin and invasion of endothelial cells. Cell. Microbiol. 3, 839–851 (2001)

    Article  CAS  Google Scholar 

  20. Talay, S. R. et al. Co-operative binding of human fibronectin to SfbI protein triggers streptococcal invasion into respiratory epithelial cells. Cell. Microbiol. 2, 521–535 (2000)

    Article  CAS  Google Scholar 

  21. Derrick, J. P. & Wigley, D. B. Crystal structure of a streptococcal protein-G domain bound to an Fab fragment. Nature 359, 752–754 (1992)

    Article  ADS  CAS  Google Scholar 

  22. Pickford, A., Smith, S., Staunton, D., Boyd, J. & Campbell, I. The hairpin structure of the 6F11F22F2 fragment from human fibronectin enhances gelatin binding. EMBO J. 20, 1519–1529 (2001)

    Article  CAS  Google Scholar 

  23. Cornilescu, G., Delaglio, F. & Bax, A. Protein backbone angle restraints from searching a database for chemical shift and sequence homology. J. Biomol. NMR 13, 289–302 (1999)

    Article  CAS  Google Scholar 

  24. Brünger, A. T. X-PLOR (Version 3.1) A System for X-ray Crystallography and NMR (Yale University, New Haven, Connecticut, 1992)

    Google Scholar 

  25. Sass, H. J., Musco, G., Stahl, S. J., Wingfield, P. T. & Grzesiek, S. Solution NMR of proteins within polyacrylamide gels: Diffusional properties and residual alignment by mechanical stress or embedding of oriented purple membranes. J. Biomol. NMR 18, 303–309 (2000)

    Article  CAS  Google Scholar 

  26. Ottiger, M., Delaglio, F. & Bax, A. Measurement of J and dipolar couplings from simplified two-dimensional NMR spectra. J. Magn. Reson. 131, 373–378 (1998)

    Article  ADS  CAS  Google Scholar 

  27. Hashimoto, Y. et al. The relative orientation of the fibronectin 6F11F2 module pair: A N-15 NMR relaxation study. J. Biomol. NMR 17, 203–214 (2000)

    Article  CAS  Google Scholar 

  28. Tjandra, N., Garrett, D. S., Gronenborn, A. M., Bax, A. & Clore, G. M. Defining long range order in NMR structure determination from the dependence of heteronuclear relaxation times on rotational diffusion anisotropy. Nature Struct. Biol. 4, 443–449 (1997)

    Article  CAS  Google Scholar 

  29. Wishart, D. S., Sykes, B. D. & Richards, F. M. The chemical-shift index—a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy. Biochemistry 31, 1647–1651 (1992)

    Article  CAS  Google Scholar 

  30. Talay, S. R., Valentin-Weigand, P., Timmis, K. N. & Chhatwal, G. S. Domain-structure and conserved epitopes of Sfb protein, the fibronectin-binding adhesin of Streptococcus pyogenes. Mol. Microbiol. 13, 531–539 (1994)

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Ulrich Schwarz-Linek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jörn M. Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew R. Pickford
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sivashankarappa Gurusiddappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jung Hwa Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ewa S. Pilka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John A. G. Briggs
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T. Sebastian Gough
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Magnus Höök
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Iain D. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jennifer R. Potts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer R. Potts.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01589

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing