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

被引:19
作者
Nishikawa, Hiroko [1 ,2 ,3 ]
Hatakeyama, Masanori [1 ,2 ,3 ]
机构
[1] Univ Tokyo, Grad Sch Med, Div Microbiol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan
[2] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan
[3] Max Planck Univ Tokyo Ctr Integrat Inflammol, Tokyo 1130033, Japan
基金
日本科学技术振兴机构;
关键词
Helicobacter pylori; CagA oncoprotein; gastric carcinoma; CagA polymorphism; EPIYA motif; CM motif; intrinsically disordered region; scaffold/hub protein; JUVENILE MYELOMONOCYTIC LEUKEMIA; MICROTUBULE-ASSOCIATED PROTEINS; TYROSINE-PHOSPHATASE; UNSTRUCTURED PROTEINS; PATHOGENICITY ISLAND; GASTRIC-CANCER; TAU-PROTEIN; PHOSPHORYLATION; KINASE; EFFECTOR;
D O I
10.3390/toxins9040136
中图分类号
TS2 [食品工业];
学科分类号
0832 ;
摘要
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.
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页数:14
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