H PYLORI CAGA INHIBITS PAR1-MARK FAMILY KINASES BY MIMICKING HOST SUBSTRATES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 work has been published: D. Neai, M.C. Miller, Z.T. Quinkert, M. Stein, B.T. Chait, and C.E. Stebbins "Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates" Nature Structural & Molecular Biology, 17(2010)130-2