Universität zu Köln

Hanisch, Franz-Georg, Bonar, David, Schloerer, Nils ORCID: 0000-0002-0990-9582 and Schroten, Horst (2014). Human Trefoil Factor 2 Is a Lectin That Binds alpha-GlcNAc-capped Mucin Glycans with Antibiotic Activity against Helicobacter pylori. J. Biol. Chem., 289 (40). S. 27363 - 27376. BETHESDA: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. ISSN 1083-351X

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Abstract

Background: Trefoil factor 2 (TFF2) forms complexes with MUC6 and is concertedly secreted by deep gastric glands. Results: TFF2 is a lectin that binds to -GlcNAc-capped MUC6 O-glycans with antibiotic activity against Helicobacter pylori. Conclusion: There may be a functional link between mucin glycans and TFF2 in H. pylori defense. Significance: The findings impact in development of defense strategies against H. pylori and in TFF2 receptor-mediated cell signaling. 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, 1,4-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 1,4-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, H-1 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 GlcNAc1-4Gal1-4GlcNAc1-6(Fuc1-2Gal1-3)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 1,4-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hanisch, Franz-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Bonar, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Schloerer, Nils UNSPECIFIED orcid.org/0000-0002-0990-9582 UNSPECIFIED Schroten, Horst UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-425936
DOI:	10.1074/jbc.M114.597757
Journal or Publication Title:	J. Biol. Chem.
Volume:	289
Number:	40
Page Range:	S. 27363 - 27376
Date:	2014
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Place of Publication:	BETHESDA
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PANCREATIC SPASMOLYTIC POLYPEPTIDE; DAMAGED GASTRIC-MUCOSA; O-LINKED GLYCANS; N-ACETYLGLUCOSAMINE; FAMILY FACTOR-2; HUMAN STOMACH; CELL MUCIN; EXPRESSION; TFF2; PEPTIDES Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42593