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

Abstract

Helicobacter pylori is a strong risk factor for stomach cancer. The CagA effector protein is translocated into host cells by a type IV secretion system and is a key virulence factor. Its effects are mediated in part through the host polarity kinase PAR1b/MARK2, which CagA binds and inhibits. The crystal structure of a complex between CagA peptide and MARK2 reveals that the CagA peptide mimics targets of this kinase family. 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.