title: Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA.
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.
authors: Division of Microbiology, Graduate School of Medicine, University of Tokyo, Japan.
authors: Takeru
authors: T
authors: Hayashi
authors: Miki
authors: M
authors: Senda
authors: Hiroko
authors: H
authors: Morohashi
authors: Hideaki
authors: H
authors: Higashi
authors: Masafumi
authors: M
authors: Horio
authors: Yui
authors: Y
authors: Kashiba
authors: Lisa
authors: L
authors: Nagase
authors: Daisuke
authors: D
authors: Sasaya
authors: Tomohiro
authors: T
authors: Shimizu
authors: Nagarajan
authors: N
authors: Venugopalan
authors: Hiroyuki
authors: H
authors: Kumeta
authors: Nobuo N
authors: NN
authors: Noda
authors: Fuyuhiko
authors: F
authors: Inagaki
authors: Toshiya
authors: T
authors: Senda
authors: Masanori
authors: M
authors: Hatakeyama
mesh_terms: D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D044463:Receptor, PAR-1 / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D044463:Receptor, PAR-1; D011994:Recombinant Proteins; C080866:cagA protein, Helicobacter pylori