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Abstract
Helicobacter pylori infection is associated with the development of gastric and duodenal ulcers as well as gastric cancer. GroES of H. pylori (HpGroES) was previously identified as a gastric cancer-associated virulence factor. Our group showed that HpGroES induces interleukin-8 (IL-8) cytokine release via a Toll-like receptor 4 (TLR4)-dependent mechanism and domain B of the protein is crucial for interactions with TLR4. In the present study, we investigated the importance of the histidine residues in domain B. To this end, a series of point mutants were expressed in Escherichia coli, and the corresponding proteins purified. Interestingly, H96, H104 and H115 were not essential, whereas H100, H102, H108, H113 and H118 were crucial for IL-8 production and TLR4 interactions in KATO-III cells. These residues were involved in nickel binding. Four of five residues, H102, H108, H113 and H118 induced certain conformation changes in extended domain B structure, which is essential for interactions with TLR4 and consequent IL-8 production. We conclude that interactions of nickel ions with histidine residues in domain B help to maintain the conformation of the C-terminal region to conserve the integrity of the HpGroES structure and modulate IL-8 release.
Highlights
Identified as a dominant gastric cancer-related antigen with significantly higher seropositivity in gastric cancer patients, compared with gastritis and duodenal ulcer patients[24]
To determine whether the histidine mutants activate IL-8, KATO-III cells were incubated with 0.05 μM WT or histidine mutant protein, and cell culture supernatants collected for measurement of IL-8 levels
Chronic H. pylori infection causes gastric cancer via the expression of virulence factors and induction of chronic inflammatory responses that result in increased levels of proinflammatory cytokines[9,10,11,12]
Summary
Identified as a dominant gastric cancer-related antigen with significantly higher seropositivity in gastric cancer patients, compared with gastritis and duodenal ulcer patients[24]. Domain B contains a histidine-rich motif with 8 histidine residues, which bind two nickel ions per GroES monomer. This metal binding ability is associated with nickel homeostasis and protection of cells from higher concentrations of nickel ion[27,28,30]. SAXS shape predictions demonstrated that HpGroES assembles into a ring-shaped homoheptamer with an internal tunnel Within this ring, these residues maintain the domain B orientation of the HpGroES structure, in turn, ensuring the correct conformation of the C-terminal region for interactions with TLR4
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