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.

Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates

Nature Structural & Molecular Biology volume 17, pages 130–132 (2010)Cite this article

Abstract

The CagA protein of Helicobacter pylori interacts with numerous cellular factors and is associated with increased virulence and risk of gastric carcinoma. We present here the cocrystal structure of a subdomain of CagA with the human kinase PAR1b/MARK2, revealing that a CagA peptide mimics substrates of this kinase family, resembling eukaryotic protein kinase inhibitors. Mutagenesis of conserved residues central to this interaction renders CagA inactive as an inhibitor of MARK2.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Figure 1: Overall structure of the CagA–MARK2 complex.
Figure 2: CagA is a pathogenic mimic of host substrates.
Figure 3: Mutational analysis of MKI mutants.

Accession codes

Primary accessions

Protein Data Bank

Referenced accessions

Protein Data Bank

References

  1. Peek, R.M. Jr. & Blaser, M.J. Nat. Rev. Cancer 2, 28–37 (2002).

    CAS  Article  Google Scholar 

  2. Censini, S., Stein, M. & Covacci, A. Curr. Opin. Microbiol. 4, 41–46 (2001).

    CAS  Article  Google Scholar 

  3. Asahi, M. et al. J. Exp. Med. 191, 593–602 (2000).

    CAS  Article  Google Scholar 

  4. Backert, S. et al. Cell. Microbiol. 2, 155–164 (2000).

    CAS  Article  Google Scholar 

  5. Odenbreit, S. et al. Science 287, 1497–1500 (2000).

    CAS  Article  Google Scholar 

  6. Stein, M., Rappuoli, R. & Covacci, A. Proc. Natl. Acad. Sci. USA 97, 1263–1268 (2000).

    CAS  Article  Google Scholar 

  7. Covacci, A. et al. Proc. Natl. Acad. Sci. USA 90, 5791–5795 (1993).

    CAS  Article  Google Scholar 

  8. Tummuru, M.K., Cover, T.L. & Blaser, M.J. Infect. Immun. 61, 1799–1809 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Saadat, I. et al. Nature 447, 330–333 (2007).

    CAS  Article  Google Scholar 

  10. Zeaiter, Z. et al. Cell. Microbiol. 10, 781–794 (2008).

    CAS  Article  Google Scholar 

  11. Higashi, H. et al. Science 295, 683–686 (2002).

    CAS  Article  Google Scholar 

  12. Panneerselvam, S., Marx, A., Mandelkow, E.M. & Mandelkow, E. Structure 14, 173–183 (2006).

    CAS  Article  Google Scholar 

  13. Huse, M. & Kuriyan, J. Cell 109, 275–282 (2002).

    CAS  Article  Google Scholar 

  14. Russo, A.A., Jeffrey, P.D. & Pavletich, N.P. Nat. Struct. Biol. 3, 696–700 (1996).

    CAS  Article  Google Scholar 

  15. Zheng, J. et al. Acta Crystallogr. D Biol. Crystallogr. 49, 362–365 (1993).

    CAS  Article  Google Scholar 

  16. Knighton, D.R. et al. Science 253, 414–420 (1991).

    CAS  Article  Google Scholar 

  17. Lu, H.S. et al. Cancer Sci. 99, 2004–2011 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank D. Oren and W. Shi for access to and assistance with crystallographic equipment. This work was funded in part by National Institutes of Health grants AI052182 (to C.E.S.) and RR00862, RR022220 (to B.T.C.), and by a Canadian Institutes of Health Research operating grant (MOP-62779) to M.S. M.S. is an Alberta Heritage Foundation for Medical Research Research Scholar.

Author information

Affiliations

  1. Laboratory of Structural Microbiology, Rockefeller University, New York, New York, USA

    Dragana Nes̆ić, Marshall C Miller & C Erec Stebbins

  2. Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, Rockefeller University, New York, New York, USA

    Zachary T Quinkert & Brian T Chait

  3. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada

    Markus Stein

Authors
  1. Dragana Nes̆ić
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marshall C Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zachary T Quinkert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Markus Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brian T Chait
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Erec Stebbins
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.N. performed all molecular biology, cloning, protein purification, functional assays, and crystallization; Z.T.Q. performed MS under the guidance of B.T.C.; M.C.M. collected crystallographic data along with D.N. and C.E.S. solved the structure. All authors contributed to writing the manuscript.

Corresponding author

Correspondence to C Erec Stebbins.

Supplementary information

Supplementary Text and Figures

Supplementary Discussion, Supplementary Methods, Supplementary Figues 1–6 and Supplementary Tables 1–4 (PDF 1035 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nes̆ić, D., Miller, M., Quinkert, Z. et al. Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates. Nat Struct Mol Biol 17, 130–132 (2010). https://doi.org/10.1038/nsmb.1705

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.1705

Further reading

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