title: Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori.
abstract: The Helicobacter pylori adhesin BabA binds mucosal ABO/Le(b) blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.
authors.affiliation: Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Moonens
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Gideonsson
authors.affiliation: Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Suresh
authors.initials: S
authors.lastname: Subedi
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Jeanna
authors.initials: J
authors.lastname: Bugaytsova
authors.affiliation: Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Ema
authors.initials: E
authors.lastname: Romaõ
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Melissa
authors.initials: M
authors.lastname: Mendez
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Nordén
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Fallah
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Rakhimova
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Shevtsova
authors.affiliation: School of Chemistry, Bangor University, Deiniol Road Bangor, Gwynedd LL57 2UW, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Lahmann
authors.affiliation: Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Castaldo
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Brännström
authors.affiliation: Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Fanny
authors.initials: F
authors.lastname: Coppens
authors.affiliation: Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Alvin W
authors.initials: AW
authors.lastname: Lo
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Tor
authors.initials: T
authors.lastname: Ny
authors.affiliation: Center for Comparative Medicine and California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA; Department of Medicine and Department of Microbiology and Immunology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Solnick
authors.affiliation: Structure and Function of Biological Membranes, Université Libre de Bruxelles, Triomflaan, 1050 Brussels, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Vandenbussche
authors.affiliation: Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Oscarson
authors.affiliation: Division of Clinical Immunology, Karolinska Institute at Karolinska University Hospital, 141 86 Huddinge, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Arnqvist
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Berg
authors.affiliation: Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Serge
authors.initials: S
authors.lastname: Muyldermans
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87, Umeå, Sweden. Electronic address: thomas.boren@umu.se.
authors.forename: Thomas
authors.initials: T
authors.lastname: Borén
authors.affiliation: Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: han.remaut@vib-vub.be.
authors.forename: Han
authors.initials: H
authors.lastname: Remaut
mesh_terms: D000017:ABO Blood-Group System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018829:Adhesins, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D016480:Helicobacter pylori / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011134:Polysaccharides / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000017:ABO Blood-Group System; D018829:Adhesins, Bacterial; C400429:BabA protein, Helicobacter pylori; D011134:Polysaccharides