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

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 co-crystal 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.

Structural insights into Helicobacter pylori oncoprotein CagA interaction with β1 integrin

“…Another remarkable characteristic of CagA N-terminal region is its flexibility, in particular the domain D1 (residues 1-300). Previously, most of the C-terminal region of CagA was found disordered, even when bound to the Par1b/MARK2 kinase (14). Here we found that domain D1, as well a number of loops of D2, D3, and D4, are highly flexible.…”

“…In particular, specific sequences (named MKI) (Fig. 1A) located in the CagA C terminus inhibit Par1b/MARK2 kinase activity via mimicry of the enzyme's natural substrate (14). The inhibition of the PAR1b/MARK2 perturbs atypical PKC signaling, which results in disruption of tight junctions and loss of cell polarity (15).…”

Characterization of the Translocation-competent Complex between the Helicobacter pylori Oncogenic Protein CagA and the Accessory Protein CagF

“…(ii) A circular dichroism spectrum of this domain shows one that is typical of a disordered protein (10). (iii) Residues 885-1005, comprising just the TPMs of CagA, resolved only 14 residues of CagA when crystallized in complex with MARK2 (28). (iv) Several intrinsic disorder prediction software programs suggest that regions of the C terminus are disordered.…”

Structure et mode d’injection de l’oncoprotéine CagA d’Helicobacter pylori

“…Ainsi, CagA se lie à la kinase MARK1 (MAP/microtubule affinity-regulating kinase 1) par l'intermédiaire de motifs (appelés MKI) situés dans la portion carboxy-terminale (Figure 1). Ces séquences miment le substrat naturel de la kinase et inhibent son activité, ce qui dérègle la polarité des cellules [4]. La partie carboxy-terminale de CagA peut être phosphorylée (CagA-P) par des kinases de la famille Src sur les tyrosines contenues dans des motifs EPIYA.…”