Molecular Evolution of the
            <i>Helicobacter pylori</i>
            Vacuolating Toxin Gene
            <i>vacA</i>

Gangwer, Kelly A.; Shaffer, Carrie L.; Suerbaum, Sebastian; Lacy, D. Borden; Cover, Timothy L.; Bordenstein, Seth R.

doi:10.1128/jb.01081-10

Cited by 51 publications

(61 citation statements)

References 55 publications

(86 reference statements)

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“…Random mutagenesis experiments revealed only two mutations in this region that abrogated VacA toxin activity (G121R and S246L) (51). Interestingly, comparative sequence analysis of VacA proteins produced by different H. pylori strains reveals heterogeneity in a region (approximately residues 144 to 244, known as the "intermediate region" or the "i-region"), which lies within the putative ␤-helical portion of p33 (23,25). H. pylori strains containing i1 forms of VacA have been linked to an elevated risk of gastric cancer, compared to strains containing i2 forms of VacA (25).…”

Section: Discussionmentioning

confidence: 99%

“…pylori strains isolated from unrelated individuals are genetically heterogeneous, and the risk of developing gastric cancer or peptic ulcer disease is determined in part by characteristics of the H. pylori strains with which persons are infected (22). All H. pylori strains contain a vacA gene, but there is a high level of sequence variation among vacA alleles from different strains (23). Several families of vacA alleles (designated s1 or s2, i1 or i2, and m1 or m2) have been described based on variation in specific regions of the gene (22,24,25).…”

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A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain

et al. 2016

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Helicobacter pylori secretes a pore-forming VacA toxin that has structural features and activities substantially different from those of other known bacterial toxins. VacA can assemble into multiple types of water-soluble flower-shaped oligomeric structures, and most VacA activities are dependent on its capacity to oligomerize. The 88-kDa secreted VacA protein can undergo limited proteolysis to yield two domains, designated p33 and p55. The p33 domain is required for membrane channel formation and intracellular toxic activities, and the p55 domain has an important role in mediating VacA binding to cells. Previous studies showed that the p55 domain has a predominantly ␤-helical structure, but no structural data are available for the p33 domain. We report here the purification and analysis of a nonoligomerizing mutant form of VacA secreted by H. pylori. The nonoligomerizing 88-kDa mutant protein retains the capacity to enter host cells but lacks detectable toxic activity. Analysis of crystals formed by the monomeric protein reveals that the ␤-helical structure of the p55 domain extends into the C-terminal portion of p33. Fitting the p88 structural model into an electron microscopy map of hexamers formed by wild-type VacA (predicted to be structurally similar to VacA membrane channels) reveals that p55 and the ␤-helical segment of p33 localize to peripheral arms but do not occupy the central region of the hexamers. We propose that the amino-terminal portion of p33 is unstructured when VacA is in a monomeric form and that it undergoes a conformational change during oligomer assembly. Helicobacter pylori is a Gram-negative bacterium that persistently colonizes the stomach in about half of the human population worldwide (1-3). Most people tolerate the presence of this organism for long periods without any adverse consequences, but a small subset of H. pylori-infected individuals develop gastric adenocarcinoma or peptic ulcer disease.H. pylori is a relatively noninvasive organism that lives in the gastric mucus layer overlying gastric epithelial cells, sometimes adhering to the gastric epithelium. Many H. pylori-induced alterations in the gastric mucosa are attributable to the actions of secreted bacterial proteins on host cells (4-6). One such protein is the secreted vacuolating toxin, VacA (4, 7-10). VacA causes multiple alterations in gastric epithelial cells, including swelling of endosomes (vacuolation) (11, 12), permeabilization of mitochondrial membranes, and activation of mitogen-activated protein kinases (4, 7-9). In addition to its effects on gastric epithelial cells, VacA can disrupt the functions of many types of immune cells (T cells, B cells, neutrophils, eosinophils, and monocytes) (4, 7-9, 13-16). The cellular activities of VacA are attributed mainly to its ability to form anion-selective channels in host cells (17-21). VacA lacks sequence similarity to any other known bacterial toxins.H. pylori strains isolated from unrelated individuals are genetically heterogeneous, and the risk of developing gastric...

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Section: Discussionmentioning

confidence: 99%

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A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain

et al. 2016

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“…Sequences were aligned, indels were removed, and pairwise comparisons were subsequently conducted using DnaSP (window size of 50 bases and step size of 10 bases). McDonald Kreitman test (MKT) analysis was conducted as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

“…Multilocus sequence typing (MLST) has revealed multiple populations and subpopulations of strains with distinct geographic distributions (20,35,39). It has been proposed that H. pylori had an African ancestral origin and subsequently spread throughout the world concurrently with human migrations (4,25,35,50).…”

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J-Western Forms of Helicobacter pylori cagA Constitute a Distinct Phylogenetic Group with a Widespread Geographic Distribution

et al. 2012

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Chronic infection with Helicobacter pylori strains expressing the bacterial oncoprotein CagA confers an increased risk of gastric cancer. While much is known about the ancestry and molecular evolution of Western, East Asian, and Amerindian cagA sequences, relatively little is understood about a fourth group, known as "J-Western," which has been detected mainly in strains from Okinawa, Japan. We show here that J-Western cagA sequences have a more widespread global distribution than previously recognized, occur in strains with multiple different ancestral origins (based on multilocus sequence typing [MLST] analysis), and did not arise recently. As shown by comparisons of Western and J-Western forms of CagA, there are 45 fixed or nearly fixed amino acid differences, and J-Western forms contain a unique 4-amino-acid insertion. The mean nucleotide diversity of synonymous sites ( s ) is slightly lower in the J-Western group than in the Western and East Asian groups (0.066, 0.086, and 0.083, respectively), which suggests that the three groups have comparable, but not equivalent, effective population sizes. The reduced s of the J-Western group is attributable to ancestral recombination events within the 5= region of cagA. Population genetic analyses suggest that within the cagA region encoding EPIYA motifs, the East Asian group underwent a marked reduction in effective population size compared to the Western and J-Western groups, in association with positive selection. Finally, we show that J-Western cagA sequences are found mainly in strains producing m2 forms of the secreted VacA toxin and propose that these functionally interacting proteins coevolved to optimize the gastric colonization capacity of H. pylori.

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Activity and Functional Importance of Helicobacter pylori Virulence Factors

Sgouras

Tegtmeyer

Weßler

2019

Advances in Experimental Medicine and Biology

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Molecular Evolution of the Helicobacter pylori Vacuolating Toxin Gene vacA

Abstract: Helicobacter pylori is a genetically diverse organism that is adapted for colonization of the human stomach.

Cited by 51 publications

References 55 publications

A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain

A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain

J-Western Forms of Helicobacter pylori cagA Constitute a Distinct Phylogenetic Group with a Widespread Geographic Distribution

Activity and Functional Importance of Helicobacter pylori Virulence Factors

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