Binding of Helicobacter pylori to Human Gastric Mucins Correlates with Binding of TFF1

Dunne, Ciara; Naughton, Julie; Duggan, Gina; Loughrey, Catherine; Kilcoyne, Michelle; Joshi, Lokesh; Carrington, Stephen D.; Earley, Helen; Backert, Steffen; Robbe-Masselot, Catherine; May, Felicity E. B.; Clyne, Marguerite

doi:10.3390/microorganisms6020044

Cited by 12 publications

(11 citation statements)

References 44 publications

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“…Thus, TFF1 seems to interact with the same mucin as TFF2 [43]. These results are in line with a study indicating that binding of TFF1 correlates with binding of H. pylori to gastric mucins recognized by the lectin GSA-II [78], i.e., MUC6 [43]. However, binding of TFF1 to MUC6 is in contrast to previous reports describing interactions with MUC5AC [79,80].…”

Section: Little Tff1 Binds To Mucin Muc6supporting

confidence: 89%

The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions

Heuer

Stürmer

et al. 2020

IJMS

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TFF1 is a protective peptide of the Trefoil Factor Family (TFF), which is co-secreted with the mucin MUC5AC, gastrokine 2 (GKN2), and IgG Fc binding protein (FCGBP) from gastric surface mucous cells. Tff1-deficient mice obligatorily develop antropyloric adenoma and about 30% progress to carcinomas, indicating that Tff1 is a tumor suppressor. As a hallmark, TFF1 contains seven cysteine residues with three disulfide bonds stabilizing the conserved TFF domain. Here, we systematically investigated the molecular forms of TFF1 in the human gastric mucosa. TFF1 mainly occurs in an unusual monomeric form, but also as a homodimer. Furthermore, minor amounts of TFF1 form heterodimers with GKN2, FCGBP, and an unknown partner protein, respectively. TFF1 also binds to the mucin MUC6 in vitro, as shown by overlay assays with synthetic 125I-labeled TFF1 homodimer. The dominant presence of a monomeric form with a free thiol group at Cys-58 is in agreement with previous studies in Xenopus laevis and mouse. Cys-58 is likely highly reactive due to flanking acid residues (PPEEEC58EF) and might act as a scavenger for extracellular reactive oxygen/nitrogen species protecting the gastric mucosa from damage by oxidative stress, e.g., H2O2 generated by dual oxidase (DUOX).

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Section: Little Tff1 Binds To Mucin Muc6supporting

confidence: 89%

The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions

Heuer

Stürmer

et al. 2020

IJMS

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“…Comparison of the interactions of TFF1 and H. pylori with purified samples of animal and human mucins [65] detected a remarkable association between the affinities of TFF1 and H. pylori for different gastric mucin preparations (Spearman’s rho = 0.81; p = 0.002). Characterisation of the accessible saccharide lectin affinities in the mucin preparations favoured by TFF1 indicated that there was a preferential interaction with terminal non-reducing α- or β-linked N-acetyl-d-glucosamine or α-(2,3)-linked sialic acid or Gal-3-SO 4 2− .…”

Section: The Interaction Of H Pylori With Tff1 Is Mediated Via Glmentioning

confidence: 99%

The Interaction of Helicobacter pylori with TFF1 and Its Role in Mediating the Tropism of the Bacteria Within the Stomach

Clyne

May

2019

IJMS

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Helicobacter pylori colonises the human stomach and has tropism for the gastric mucin, MUC5AC. The majority of organisms live in the adherent mucus layer within their preferred location, close to the epithelial surface where the pH is near neutral. Trefoil factor 1 (TFF1) is a small trefoil protein co-expressed with the gastric mucin MUC5AC in surface foveolar cells and co-secreted with MUC5AC into gastric mucus. Helicobacter pylori binds with greater avidity to TFF1 dimer, which is present in gastric mucus, than to TFF1 monomer. Binding of H. pylori to TFF1 is mediated by the core oligosaccharide subunit of H. pylori lipopolysaccharide at pH 5.0–6.0. Treatment of H. pylori lipopolysaccharide with mannosidase or glucosidase inhibits its interaction with TFF1. Both TFF1 and H. pylori have a propensity for binding to mucins with terminal non-reducing α- or β-linked N-acetyl-d-glucosamine or α-(2,3) linked sialic acid or Gal-3-SO42−. These findings are strong evidence that TFF1 has carbohydrate-binding properties that may involve a conserved patch of aromatic hydrophobic residues on the surface of its trefoil domain. The pH-dependent lectin properties of TFF1 may serve to locate H. pylori deep in the gastric mucus layer close to the epithelium rather than at the epithelial surface. This restricted localisation could limit the interaction of H. pylori with epithelial cells and the subsequent host signalling events that promote inflammation.

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“…1b) 21 . A lectin-like activity has also been reported for TFF1, which binds Helicobacter pylori lipopolysaccharide (LPS) in an α-glucosidase-sensitive manner 22 , and gastric mucin 23 . While unique protein-protein interactions may occur between the TFFs and their many reported binding partners 24 , a TFF lectin activity would also explain their association with such a diverse array of glycoproteins.…”

mentioning

confidence: 93%

Trefoil factors share a lectin activity that defines their role in mucus

et al. 2020

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The mucosal epithelium secretes a host of protective disulfide-rich peptides, including the trefoil factors (TFFs). The TFFs increase the viscoelasticity of the mucosa and promote cell migration, though the molecular mechanisms underlying these functions have remained poorly defined. Here, we demonstrate that all TFFs are divalent lectins that recognise the GlcNAc-α-1,4-Gal disaccharide, which terminates some mucin-like O-glycans. Degradation of this disaccharide by a glycoside hydrolase abrogates TFF binding to mucins. Structural, mutagenic and biophysical data provide insights into how the TFFs recognise this disaccharide and rationalise their ability to modulate the physical properties of mucus across different pH ranges. These data reveal that TFF activity is dependent on the glycosylation state of mucosal glycoproteins and alludes to a lectin function for trefoil domains in other human proteins.

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Binding of Helicobacter pylori to Human Gastric Mucins Correlates with Binding of TFF1

Cited by 12 publications

References 44 publications

The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions

The Tumor Suppressor TFF1 Occurs in Different Forms and Interacts with Multiple Partners in the Human Gastric Mucus Barrier: Indications for Diverse Protective Functions

The Interaction of Helicobacter pylori with TFF1 and Its Role in Mediating the Tropism of the Bacteria Within the Stomach

Trefoil factors share a lectin activity that defines their role in mucus

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