- Cytotoxin-associated gene A (CagA), encoded by Helicobacter pylori, is one of the bacterium’s most potent virulence factors. It plays a pivotal role in the development of various gastric diseases, including gastritis, peptic ulcers, and gastric adenocarcinoma. Once translocated into gastric epithelial cells via the bacterial type IV secretion system (T4SS), CagA becomes phosphorylated and engages multiple host signaling proteins, thereby subverting normal cellular function.
- Structurally, CagA is composed of two distinct regions: a relatively conserved and structured N-terminal region and a highly variable, intrinsically disordered C-terminal region.
- The N-terminal region constitutes approximately 70% of the protein and is organized into three structural domains, Domain I, Domain II, and Domain III, each with specific roles in CagA’s intracellular activity.
- Domain I is known to be structurally flexible and harbors a three-helix bundle critical for binding to apoptosis-stimulating protein of p53-2 (ASPP2). This interaction stabilizes the domain and enhances its affinity for tumor suppressor proteins such as p53, thereby influencing apoptosis and cellular stress responses.
- Domain II contains a large anti-parallel β-sheet and a basic phosphatidylserine-binding motif (K-Xₙ-R-X-R), which facilitates membrane localization of CagA, especially in polarized epithelial cells. This membrane tethering is essential for its downstream signaling functions.
- Domain III contains a hydrophobic N-terminal binding sequence (NBS) that interacts with a C-terminal binding sequence (CBS) located in the disordered region of the protein. This interaction forms a topologically unique lasso-like structure that stabilizes the protein’s overall conformation and enhances its scaffold-like activity, allowing for the recruitment of multiple host signaling proteins.
- The C-terminal region, accounting for about 30% of the total protein, is rich in functional motifs and shows high variability among different H. pylori strains. Two critical types of motifs within this region are the EPIYA motifs and the CagA multimerization (CM) motifs.
- The EPIYA motifs—short amino acid sequences with the consensus Glu-Pro-Ile-Tyr-Ala—are subject to tyrosine phosphorylation by host kinases such as Src and Abl. These motifs are classified as EPIYA-A, -B, -C, or -D, depending on their flanking sequences. Western strains of H. pylori typically contain EPIYA-C repeats, while East Asian strains predominantly feature the more virulent EPIYA-D segment.
- Once phosphorylated, EPIYA-C and especially EPIYA-D motifs bind with high affinity to SHP2, a host tyrosine phosphatase involved in key signaling pathways such as RAS-ERK. This interaction results in aberrant activation of SHP2, leading to enhanced cell proliferation, cytoskeletal rearrangement, and oncogenic transformation. Notably, the stronger SHP2 activation observed in East Asian strains correlates with higher incidences of gastric cancer in these populations.
- CM motifs, on the other hand, mediate multimerization of CagA within the host cytoplasm. These motifs facilitate interactions with host polarity-regulating proteins such as PAR1b (also known as MARK2), a serine/threonine kinase involved in maintaining epithelial cell polarity and tight junction organization. Multimerization enhances the disruptive effects of CagA on cell architecture, contributing to cellular elongation (the so-called “hummingbird phenotype”), loss of apicobasal polarity, and increased migratory behavior of epithelial cells—features associated with epithelial-mesenchymal transition and malignancy.
- Importantly, the structural diversity in the C-terminal region underlies the strain-dependent differences in virulence. For example, Western CagA variants often contain multiple EPIYA-C and CM motifs, while East Asian strains usually carry a single, highly active EPIYA-D motif. This molecular variability helps explain the different clinical outcomes associated with infection by different H. pylori strains.
- In conclusion, the modular architecture of CagA—with a structured N-terminal region for membrane interaction and scaffold function, and a flexible C-terminal region for host signaling subversion—enables it to act as a multifunctional effector protein. Its capacity to engage in both phosphorylation-dependent and -independent interactions with host cell proteins makes it central to the pathogenesis of H. pylori-associated gastric disease. A deeper understanding of CagA’s structure-function relationships provides key insights into microbial oncogenesis and offers potential targets for therapeutic intervention.
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