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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.

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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.

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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.

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Authors and 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

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  1. Dragana Nes̆ić
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  2. Marshall C Miller
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  3. Zachary T Quinkert
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  4. Markus Stein
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  6. C Erec Stebbins
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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.

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Correspondence to C Erec Stebbins.

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

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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

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