Structure-based analysis of biological activity of Helicobacter pylori CagA

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Helicobacter pylori CagA protein is injected into gastric epithelial cells, where it interacts with cellular proteins such as SHP-2 and Par1 through its C-terminal region containing Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Consequently, CagA perturbs intracellular machineries involved in the regulation of cell growth and cell polarity. To elucidate molecular basis for the pathophysiological activity of CagA, we sought to determine three-dimensional structure of CagA. We performed a limited proteolysis experiment of CagA and identified a specific cleavage site, which could represent a linker region that connects the possible N-terminal and C-terminal structural domains of CagA. Intriguingly, the C-terminal proteolytic fragment of CagA was bound to the remaining N-terminal proteolytic fragment. Furthermore, we found that N-terminal fragment enhances CagA biological activity that induces cell morphological changes in depending on the C-terminal region of CagA. Our finding indicates that an intramolecular interaction between the N-terminal and C-terminal domains plays an important role in the structural integrity of the biologically active CagA protein.