title: Human trefoil factor 2 is a lectin that binds α-GlcNAc-capped mucin glycans with antibiotic activity against Helicobacter pylori.
abstract: Helicobacter pylori infection is the major cause of gastric cancer and remains an important health care challenge. The trefoil factor peptides are a family of small highly conserved proteins that are claimed to play essential roles in cytoprotection and epithelial repair within the gastrointestinal tract. H. pylori colocalizes with MUC5AC at the gastric surface epithelium, but not with MUC6 secreted in concert with TFF2 by deep gastric glands. Both components of the gastric gland secretome associate non-covalently and show increased expression upon H. pylori infection. Although blood group active O-glycans of the Lewis-type form the basis of H. pylori adhesion to the surface mucin layer and to epithelial cells, α1,4-GlcNAc-capped O-glycans on gastric mucins were proposed to inhibit H. pylori growth as a natural antibiotic. We show here that the gastric glycoform of TFF2 is a calcium-independent lectin, which binds with high specificity to O-linked α1,4-GlcNAc-capped hexasaccharides on human and porcine stomach mucin. The structural assignments of two hexasaccharide isomers and the binding active glycotope were based on mass spectrometry, linkage analysis, (1)H nuclear magnetic resonance spectroscopy, glycan inhibition, and lectin competition of TFF2-mucin binding. Neoglycolipids derived from the C3/C6-linked branches of the two isomers revealed highly specific TFF2 binding to the 6-linked trisaccharide in GlcNAcα1-4Galβ1-4GlcNAcβ1-6(Fucα1-2Galβ1-3)GalNAc-ol(Structure 1). Supposedly, lectin TFF2 is involved in protection of gastric epithelia via a functional relationship to defense against H. pylori launched by antibiotic α1,4-GlcNAc-capped mucin glycans. Lectin-carbohydrate interaction may have also an impact on more general functional aspects of TFF members by mediating their binding to cell signaling receptors.
authors.affiliation: From the Institute of Biochemistry II, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Köln, the Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Str. 21, 50931 Köln, franz.hanisch@uni-koeln.de.
authors.forename: Franz-Georg
authors.initials: FG
authors.lastname: Hanisch
authors.affiliation: From the Institute of Biochemistry II, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Köln.
authors.forename: David
authors.initials: D
authors.lastname: Bonar
authors.affiliation: the Institute of Organic Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, and.
authors.forename: Nils
authors.initials: N
authors.lastname: Schloerer
authors.affiliation: the University Children's Hospital, Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Schroten
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D002240:Carbohydrate Sequence; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D055272:Mucin-6 / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D013552:Swine; D000071164:Trefoil Factor-2
chemical_list: C524734:MUC6 protein, human; D055272:Mucin-6; D010455:Peptides; D011134:Polysaccharides; C000604007:TFF2 protein, human; D000071164:Trefoil Factor-2; D000117:Acetylglucosamine
keywords: Glycomics; Glycosylation; Helicobacter pylori; Lectin; Mucin; Mucin-type O-Glycans; Trefoil Factor Family 2 (TFF2)