Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA |
| |
Authors: | Takeru Hayashi Miki Senda Hiroko Morohashi Hideaki Higashi Masafumi Horio Yui Kashiba Lisa Nagase Daisuke Sasaya Tomohiro Shimizu Nagarajan Venugopalan Hiroyuki Kumeta Nobuo N Noda Fuyuhiko Inagaki Toshiya Senda Masanori Hatakeyama |
| |
Affiliation: | Division of Microbiology, Graduate School of Medicine, University of Tokyo, Japan. |
| |
Abstract: | The Helicobacter pylori type IV secretion effector CagA is a major bacterial virulence determinant and critical for gastric carcinogenesis. Upon delivery into gastric epithelial cells, CagA localizes to the inner face of the plasma membrane, where it acts as a pathogenic scaffold/hub that promiscuously recruits host proteins to potentiate oncogenic signaling. We find that CagA comprises a structured N-terminal region and an intrinsically disordered C-terminal region that directs versatile protein interactions. X-ray crystallographic analysis of the N-terminal CagA fragment (residues 1-876) revealed that the region has a structure comprised of three discrete domains. Domain I constitutes a mobile CagA N terminus, while Domain II tethers CagA to the plasma membrane by interacting with membrane phosphatidylserine. Domain III interacts intramolecularly with the intrinsically disordered C-terminal region, and this interaction potentiates the pathogenic scaffold/hub function of CagA. The present work provides a tertiary-structural basis for the pathophysiological/oncogenic action of H. pylori CagA. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|