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:

Crystal structure of a complex between anthrax toxin and its host cell receptor

Nature volume 430, pages 905–908 (2004)Cite this article

Abstract

Anthrax toxin consists of the proteins protective antigen (PA), lethal factor (LF) and oedema factor (EF)1. The first step of toxin entry into host cells is the recognition by PA of a receptor on the surface of the target cell. Subsequent cleavage of receptor-bound PA enables EF and LF to bind and form a heptameric PA63 pre-pore, which triggers endocytosis. Upon acidification of the endosome, PA63 forms a pore that inserts into the membrane and translocates EF and LF into the cytosol2. Two closely related host cell receptors, TEM8 and CMG2, have been identified. Both bind to PA with high affinity and are capable of mediating toxicity3,4. Here, we report the crystal structure of the PA–CMG2 complex at 2.5 Å resolution. The structure reveals an extensive receptor–pathogen interaction surface mimicking the non-pathogenic recognition of the extracellular matrix by integrins5. The binding surface is closely conserved in the two receptors and across species, but is quite different in the integrin domains, explaining the specificity of the interaction. CMG2 engages two domains of PA, and modelling of the receptor-bound PA63 heptamer6,7,8 suggests that the receptor acts as a pH-sensitive brace to ensure accurate and timely membrane insertion. The structure provides new leads for the discovery of anthrax anti-toxins, and should aid the design of cancer therapeutics9.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Structure of the PA–CMG2 complex.
Figure 2: The MIDAS motifs of the PA–CMG2 complex (a) and the collagen–integrin α2β1 complex5 (b).
Figure 3: Intermolecular contacts between PA domains II and IV and CMG2.
Figure 4: Key elements of the PA–CMG2 interaction a, Solvent-accessible surface of the PA domain IV groove, with key side chains from three CMG2 loops (β1–α1, blue; β2–β3, red; α2–α3, green) shown in ball-and-stick representation.
Figure 5: Hypothetical model of the receptor-bound, membrane-inserted PA pore.

Similar content being viewed by others

References

  1. Moayeri, M. & Leppla, S. H. The roles of anthrax toxin in pathogenesis. Curr. Opin. Microbiol. 7, 19–24 (2004)

    Article  CAS  Google Scholar 

  2. Abrami, L., Liu, S., Cosson, P., Leppla, S. H. & Vander Goot, F. G. Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process. J. Cell Biol. 160, 321–328 (2003)

    Article  CAS  Google Scholar 

  3. Bradley, K. A., Mogridge, J., Mourez, M., Collier, R. J. & Young, J. A. Identification of the cellular receptor for anthrax toxin. Nature 414, 225–229 (2001)

    Article  ADS  CAS  Google Scholar 

  4. Scobie, H. M., Rainey, G. J., Bradley, K. A. & Young, J. A. Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. Proc. Natl Acad. Sci. USA 100, 5170–5174 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Emsley, J., Knight, C. G., Farndale, R. W., Barnes, M. J. & Liddington, R. C. Structural basis of collagen recognition by integrin α2β1. Cell 101, 47–56 (2000)

    Article  CAS  Google Scholar 

  6. Petosa, C., Collier, R. J., Klimpel, K. R., Leppla, S. H. & Liddington, R. C. Crystal structure of the anthrax toxin protective antigen. Nature 385, 833–838 (1997)

    Article  ADS  CAS  Google Scholar 

  7. Benson, E. L., Huynh, P. D., Finkelstein, A. & Collier, R. J. Identification of residues lining the anthrax protective antigen channel. Biochemistry 37, 3941–3948 (1998)

    Article  CAS  Google Scholar 

  8. Nassi, S., Collier, R. J. & Finkelstein, A. PA63 channel of anthrax toxin: an extended β-barrel. Biochemistry 41, 1445–1450 (2002)

    Article  CAS  Google Scholar 

  9. Frankel, A. E., Koo, H.-K., Leppla, S. H., Duesbury, N. S. & Vande Woude, G. F. Novel protein targeted therapy of metastatic melanoma. Curr. Pharm. Des. 9, 2060–2066 (2003)

    Article  CAS  Google Scholar 

  10. Lee, J.-O., Rieu, P., Arnaout, M. A. & Liddington, R. C. Crystal structure of the A-domain from the α subunit of integrin CR3 (CD11b/CD18). Cell 80, 631–635 (1995)

    Article  CAS  Google Scholar 

  11. Lacy, D. B., Wigelsworth, D. J., Scobie, H. M., Young, J. A. & Collier, R. J. Crystal structure of the von Willebrand factor A domain of human capillary morphogenesis protein 2: An anthrax toxin receptor. Proc. Natl Acad. Sci. USA 101, 6367–6372 (2004)

    Article  ADS  CAS  Google Scholar 

  12. Wigelsworth, D. J. et al. Binding stoichiometry and kinetics of the interaction of a human anthrax toxin receptor, CMG2, with protective antigen. J. Biol. Chem. 279, 23349–23356 (2004)

    Article  CAS  Google Scholar 

  13. Shimaoka, M. et al. Structures of the αL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 112, 99–111 (2003)

    Article  CAS  Google Scholar 

  14. Rosovitz, M. J. et al. Alanine scanning mutations in domain 4 of anthrax toxin protective antigen reveal residues important for binding to the cellular receptor and to a neutralizing monoclonal antibody. J. Biol. Chem. 278, 30936–30944 (2003)

    Article  CAS  Google Scholar 

  15. Bradley, K. A. et al. Binding of anthrax toxin to its receptor is similar to α integrin-ligand interactions. J. Biol. Chem. 278, 49342–49347 (2003)

    Article  CAS  Google Scholar 

  16. Mourez, M. et al. Mapping dominant-negative mutations of anthrax protective antigen by scanning mutagenesis. Proc. Natl Acad. Sci. USA 100, 13803–13808 (2003)

    Article  ADS  CAS  Google Scholar 

  17. Miller, C. J., Elliott, J. L. & Collier, R. J. Anthrax protective antigen: prepore-to-pore conversion. Biochemistry 38, 10432–10441 (1999)

    Article  CAS  Google Scholar 

  18. Petosa, C. in Crystal Structure of the Anthrax Protective Antigen. Thesis, Harvard Univ (1995)

    Google Scholar 

  19. Song, L. et al. Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore. Science 274, 1859–1866 (1996)

    Article  ADS  CAS  Google Scholar 

  20. Nanda, A. & St Croix, B. Tumor endothelial markers: new targets for cancer therapy. Curr. Opin. Oncol. 16, 44–49 (2004)

    Article  CAS  Google Scholar 

  21. Nanda, A. et al. TEM8 interacts with the cleaved C5 domain of collagen alpha 3(VI). Cancer Res. 64, 817–820 (2004)

    Article  CAS  Google Scholar 

  22. Liu, S., Schubert, R. L., Bugge, T. H. & Leppla, S. H. Anthrax toxin: structures, functions and tumour targeting. Expert Opin. Biol. Ther. 3, 843–853 (2003)

    Article  CAS  Google Scholar 

  23. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

    Article  CAS  Google Scholar 

  24. Collaborative Computational Project, No. 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)

    Article  Google Scholar 

  25. Jones, T. A., Zou, J.-Y., Cowan, S. W. & Kjelgaard, M. Improved methods for building protein models into electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991)

    Article  Google Scholar 

  26. Morris, R. J., Perrakis, A. & Lamzin, V. S. ARP/wARP and automatic interpretation of protein electron density maps. Methods Enzymol. 374, 229–244 (2003)

    Article  CAS  Google Scholar 

  27. Brunger, A. T. et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    Article  CAS  Google Scholar 

  28. Lee, J.-O., Bankston, L. A., Arnaout, M. A. & Liddington, R. C. Two conformations of the integrin A-domain (I-domain): a pathway for activation? Structure 3, 1333–1340 (1995)

    Article  CAS  Google Scholar 

  29. Sanner, M. F., Olson, A. J. & Spehner, J. C. Reduced surface: an efficient way to compute molecular surfaces. Biopolymers 38, 305–320 (1996)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the NIH and the DOD for financial support, and the DOE and staff at the SSRL for synchrotron access and support.

Author information

Authors and Affiliations

  1. Program on Cell Adhesion, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California, 92037, USA

    Eugenio Santelli, Laurie A. Bankston & Robert C. Liddington

  2. Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, 20892, USA

    Stephen H. Leppla

Authors
  1. Eugenio Santelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurie A. Bankston
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen H. Leppla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert C. Liddington
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert C. Liddington.

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

Santelli, E., Bankston, L., Leppla, S. et al. Crystal structure of a complex between anthrax toxin and its host cell receptor. Nature 430, 905–908 (2004). https://doi.org/10.1038/nature02763

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02763

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