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Toxins 2017, 9(4), 136; doi:10.3390/toxins9040136

Sequence Polymorphism and Intrinsic Structural Disorder as Related to Pathobiological Performance of the Helicobacter pylori CagA Oncoprotein

1
Division of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
2
CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan
3
Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Jean E. Crabtree and Silja Wessler
Received: 1 March 2017 / Revised: 8 April 2017 / Accepted: 10 April 2017 / Published: 13 April 2017
(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)
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Abstract

CagA, an oncogenic virulence factor produced by Helicobacter pylori, is causally associated with the development of gastrointestinal diseases such as chronic gastritis, peptic ulcers, and gastric cancer. Upon delivery into gastric epithelial cells via bacterial type IV secretion, CagA interacts with a number of host proteins through the intrinsically disordered C-terminal tail, which contains two repeatable protein-binding motifs, the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif and the CagA multimerization (CM) motif. The EPIYA motif, upon phosphorylation by host kinases, binds and deregulates Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), a bona fide oncoprotein, inducing pro-oncogenic mitogenic signaling and abnormal cell morphology. Through the CM motif, CagA inhibits the kinase activity of polarity regulator partitioning-defective 1b (PAR1b), causing junctional and polarity defects while inducing actin cytoskeletal rearrangements. The magnitude of the pathobiological action of individual CagA has been linked to the tandem repeat polymorphisms of these two binding motifs, yet the molecular mechanisms by which they affect disease outcome remain unclear. Recent studies using quantitative techniques have provided new insights into how the sequence polymorphisms in the structurally disordered C-terminal region determine the degree of pro-oncogenic action of CagA in the gastric epithelium. View Full-Text
Keywords: Helicobacter pylori; CagA oncoprotein; gastric carcinoma; CagA polymorphism; EPIYA motif; CM motif; intrinsically disordered region; scaffold/hub protein Helicobacter pylori; CagA oncoprotein; gastric carcinoma; CagA polymorphism; EPIYA motif; CM motif; intrinsically disordered region; scaffold/hub protein
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Nishikawa, H.; Hatakeyama, M. Sequence Polymorphism and Intrinsic Structural Disorder as Related to Pathobiological Performance of the Helicobacter pylori CagA Oncoprotein. Toxins 2017, 9, 136.

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