Crystal structure of CagL from Helicobacter pylori K74 strain

Choi, Jin Kyeong; Choi, Yun Hui; Sudhanva, Muddenahalli Srinivasa; Sundaravinayagam, Devakumar; Lee, Kun Ho; Heon, Jeong; Lee, Sung Haeng

doi:10.1016/j.bbrc.2015.03.135

Cited by 14 publications

(16 citation statements)

References 24 publications

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“…Template-based structural modelling of the CagL TSPSA deletion mutant also suggested a slight repositioning of the α2 helix with regard to α1 and the intrinsic turn of helix α2. In line with this, recent structural data3242 support the hypothesis that the position of α2 and the relative orientation of helix α2 versus helix α1 are important for the RGD motif to be in the correct orientation to optimally interact with integrins. This conformational flexibility impacts on CagL integrin binding, in particular at low pH as recently demonstrated32.…”

Section: Discussionsupporting

confidence: 53%

“…Integrin can be bound by the RGD motif in CagL272932 and RGD-independently by other cag PAI proteins33, and is involved in CagA translocation. Based on 3D structural modelling of CagL loop regions, confirmed by several recently clarified crystal structure variants of CagL32373842, the analysis of global H. pylori inter-strain variation, and the comparison of H. pylori CagL with other potential bacterial orthologs, we have formed the hypothesis that unique loop regions in CagL harbor as yet unknown functions. We have therefore aimed in the present study at defining novel CagL motifs which can be involved in functions of CagL with regard to the CagT4SS and host cell interaction.…”

Section: Discussionmentioning

confidence: 73%

“…Transferring certain mutations in this region to a reference strain and testing these on host cells as has in part been done already46 might offer more clues as to whether these variations modulate the interaction of CagL with host cells. In addition, strain-specific structural differences in CagL variants, for example disulphide bridges, which can confer higher stability at lower pH42 are suggestive to be the result of functionally diversifying evolution.…”

Section: Discussionmentioning

confidence: 99%

“…Only two proposed VirB5 proteins of T4SS have been structurally characterized so far, TraC, which is a remote ortholog from a DNA conjugation system in Escherichia coli 26 and CagL374232. While TraC26 and CagL37 are not very similar in structure, they exhibit common features such as a high content in alpha helices, arranged in an antiparallel conformation.…”

Section: Discussionmentioning

confidence: 99%

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Systematic site-directed mutagenesis of the Helicobacter pylori CagL protein of the Cag type IV secretion system identifies novel functional domains

Bönig

Olbermann

Bats

et al. 2016

Sci Rep

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The Cag Type IV secretion system, which contributes to inflammation and cancerogenesis during chronic infection, is one of the major virulence factors of the bacterial gastric pathogen Helicobacter pylori. We have generated and characterized a series of non-marked site-directed chromosomal mutants in H. pylori to define domains of unknown function of the essential tip protein CagL of the Cag secretion system. Characterizing the CagL mutants, we determined that their function to activate cells and transport the effector CagA was reduced to different extents. We identified three novel regions of the CagL protein, involved in its structural integrity, its possible interaction with the CagPAI T4SS pilus protein CagI, and in its binding to integrins and other host cell ligands. In particular two novel variable CagL motifs were involved in integrin binding, TSPSA, and TASLI, which is located opposite of its integrin binding motif RGD. We thereby defined functionally important subdomains within the CagL structure, which can be used to clarify CagL contributions in the context of other CagPAI proteins or for inhibition of the CagT4SS. This structure-function correlation of CagL domains can also be instructive for the functional characterization of other potential VirB5 orthologs whose structure is not yet known.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Systematic site-directed mutagenesis of the Helicobacter pylori CagL protein of the Cag type IV secretion system identifies novel functional domains

Bönig

Olbermann

Bats

et al. 2016

Sci Rep

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“…These findings highlight some specialized features of the T4SS, which are probably optimized for function in the gastric environment . In addition, the crystal structure of CagL of East Asian strain K74 was published and a comparison with CagL of the Western strain 26 695 revealed two additional salt bridges . Furthermore, it was reported that the RGD motif in CagL is buried at low pH conditions.…”

Section: Type IV Secretion System and Cagl Crystal Structuresmentioning

confidence: 70%

Pathogenesis of Helicobacter pylori infection

et al. 2016

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Helicobacter pylori is estimated to infect more than half of the worlds human population and represents a major risk factor for chronic gastritis, peptic ulcer disease, MALT lymphoma, and gastric adenocarcinoma. H. pylori infection and clinical consequences are controlled by highly complex interactions between the host, colonizing bacteria, and environmental parameters. Important bacterial determinants linked with gastric disease development include the cag pathogenicity island encoding a type IV secretion system (T4SS), the translocated effector protein CagA, vacuolating cytotoxin VacA, adhesin BabA, urease, serine protease HtrA, secreted outer membrane vesicles, and many others. The high quantity of these factors and allelic changes in the corresponding genes reveals a sophisticated picture and problems in evaluating the impact of each distinct component. Extensive work has been performed to pinpoint molecular processes related to H. pylori-triggered pathogenesis using Mongolian gerbils, mice, primary tissues, as well as novel in vitro model systems such as gastroids. The manipulation of host signaling cascades by the bacterium appears to be crucial for inducing pathogenic downstream activities and gastric disease progression. Here, we review the most recent advances in this important research area.

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Genetic polymorphisms in the cag pathogenicity island of Helicobacter pylori and risk of stomach cancer and high‐grade premalignant gastric lesions

Canzian

Rizzato

Obazee

et al. 2020

Intl Journal of Cancer

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Helicobacter pylori (Hp) infects the stomach of about half of the human population and is strongly associated with the risk of gastric cancer (GC) and its premalignant precursors. The cag pathogenicity island (cagPAI) is a region of the Hp genome encoding for key molecular machinery involved in the infection process. Following a sequencing study, we selected 50 genetic polymorphisms located in seven cagPAI genes and tested their associations with the risk of advanced gastric premalignant lesions and GC in 1220 subjects from various Latin American populations showing the whole spectrum of phenotypes from gastritis to GC. We found that three polymorphisms of cagA are associated with the risk of advanced gastric premalignant lesions (incomplete intestinal metaplasia [ie, Type 2 and 3] or dysplasia), and that six polymorphisms located in cagA, cagL and cagI were associated with risk of GC. When corrected for multiple testing none of the associations were statistically significant. However, scores built by integrating the individual polymorphisms were significantly associated with the risk of advanced gastric premalignant lesions and GC. These results have the potential of establishing markers for risk stratification in the general population, in view of targeting Hp eradication to high‐risk population groups.

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Crystal structure of CagL from Helicobacter pylori K74 strain

Cited by 14 publications

References 24 publications

Systematic site-directed mutagenesis of the Helicobacter pylori CagL protein of the Cag type IV secretion system identifies novel functional domains

Systematic site-directed mutagenesis of the Helicobacter pylori CagL protein of the Cag type IV secretion system identifies novel functional domains

Pathogenesis of Helicobacter pylori infection

Genetic polymorphisms in the cag pathogenicity island of Helicobacter pylori and risk of stomach cancer and high‐grade premalignant gastric lesions

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