Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2

Significance Helicobacter pylori is the greatest risk factor for gastric adenocarcinoma and has been classified as a carcinogen by the World Health Organization. Cytotoxin associated gene A (CagA) is the primary virulence determinant of H. pylori and is sufficient to induce tumor formation in animal models. We show here that the host tumor suppressor Apoptosis-stimulating Protein of p53-2 (ASPP2) binds robustly to an N-terminal domain of CagA and elucidate the crystal structure of this complex, revealing the details of the CagA–ASPP2 interaction. Structure-based mutagenesis disrupts this complex in vitro and in cells. Furthermore, we show that the CagA–ASPP2 interaction modulates critical ASPP2 functions, such as p53-binding and apoptosis of H. pylori -infected cells.