title: Impact of structural polymorphism for the Helicobacter pylori CagA oncoprotein on binding to polarity-regulating kinase PAR1b.
abstract: Chronic infection with cagA-positive Helicobacter pylori is the strongest risk factor for atrophic gastritis, peptic ulcers, and gastric cancer. CagA, the product of the cagA gene, is a bacterial oncoprotein, which, upon delivery into gastric epithelial cells, binds to and inhibits the polarity-regulating kinase, partitioning-defective 1b (PAR1b) [also known as microtubule affinity-regulating kinase 2 (MARK2)], via its CagA multimerization (CM) motif. The inhibition of PAR1b elicits junctional and polarity defects, rendering cells susceptible to oncogenesis. Notably, the polymorphism in the CM motif has been identified among geographic variants of CagA, differing in either the copy number or the sequence composition. In this study, through quantitative analysis of the complex formation between CagA and PAR1b, we found that several CagA species have acquired elevated PAR1b-binding activity via duplication of the CM motifs, while others have lost their PAR1b-binding activity. We also found that strength of CagA-PAR1b interaction was proportional to the degrees of stress fiber formation and tight junctional disruption by CagA in gastric epithelial cells. These results indicate that the CM polymorphism is a determinant for the magnitude of CagA-mediated deregulation of the cytoskeletal system and thereby possibly affects disease outcome of cagA-positive H. pylori infection, including gastric cancer.
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.|Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: College of Bioresource Sciences, Nihon University, Fujisawa 252-0880, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Arisaka
authors.affiliation: CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.|Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Senda
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.|Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
mesh_terms: D020816:Amino Acid Motifs; D000942:Antigens, Bacterial / Q000235:genetics* / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D015513:Oncogene Proteins; C080866:cagA protein, Helicobacter pylori; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases