The Three-dimensional Structure of the Extracellular Adhesion Domain of the Sialic Acid-binding Adhesin SabA from Helicobacter pylori

Pang, Siew Siew; Nguyen, Stanley Thai Son; Perry, Andrew; Day, Christopher J.; Panjikar, Santosh; Tiralongo, Joe; Whisstock, James C.; Kwok, Terry

doi:10.1074/jbc.m113.513135

Cited by 56 publications

(51 citation statements)

References 30 publications

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“…Thus, it seems likely that the N-terminal portions of many protease-susceptible H. pylori OMPs differ in structure compared to most known autotransporter passenger domains. In support of this view, a recent X-ray crystallographic study of the N-terminal region of H. pylori SabA (an OMP that is related to BabA, but not produced by the H. pylori strain analyzed in this study) revealed primarily ␣-helical motifs instead of the ␤-helical motifs characteristic of most autotransporter passenger domains (54,56).…”

Section: Discussionmentioning

confidence: 82%

Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori

et al. 2014

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More than 50Helicobacter pylori genes are predicted to encode outer membrane proteins (OMPs), but there has been relatively little experimental investigation of the H. pylori cell surface proteome. In this study, we used selective biotinylation to label proteins localized to the surface of H. pylori, along with differential detergent extraction procedures to isolate proteins localized to the outer membrane. Proteins that met multiple criteria for surface-exposed outer membrane localization included known adhesins, as well as Cag proteins required for activity of the cag type IV secretion system, putative lipoproteins, and other proteins not previously recognized as cell surface components. We identified sites of nontryptic cleavage consistent with signal sequence cleavage, as well as C-terminal motifs that may be important for protein localization. A subset of surface-exposed proteins were highly susceptible to proteolysis when intact bacteria were treated with proteinase K. Most Hop and Hom OMPs were susceptible to proteolysis, whereas Hor and Hof proteins were relatively resistant. Most of the protease-susceptible OMPs contain a large protease-susceptible extracellular domain exported beyond the outer membrane and a protease-resistant domain at the C terminus with a predicted ␤-barrel structure. These features suggest that, similar to the secretion of the VacA passenger domain, the N-terminal domains of protease-susceptible OMPs are exported through an autotransporter pathway. Collectively, these results provide new insights into the repertoire of surface-exposed H. pylori proteins that may mediate bacterium-host interactions, as well as the cell surface topology of these proteins.

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Section: Discussionmentioning

confidence: 82%

Analysis of Surface-Exposed Outer Membrane Proteins in Helicobacter pylori

et al. 2014

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“…The X-ray structures of the BabA AD in complex with Nb-ER14 or Nb-ER19 showed that BabA's ectodomain comprises a core domain consisting of seven α helices organized in a joined 4-helix (H2, H6, H7, H9) plus 3-helix (H3, H4, H5) bundle (hereafter referred to as 4+3-helix bundle) (Figures 2A and S1D; Table S2). Multiple sequence alignment (MSA) of Hop proteins and superimposition of BabA AD on the SabA ectodomain structure (SabA binds sialyl-lactose and sialylated Lewis antigens as sLe x and sLe a found in inflamed gatric tissues; Mahdavi et al, 2002; PDB: 4O5J; Pang et al, 2014; Figure S2) suggest that the 4+3-helix bundle topology is conserved among most Hop members. In SabA and a recently reported structure of the extracellular domain of strain J99 BabA (Hage et al, 2015), an additional α-helical coiled-coil domain is seen at a right angle to the 4+3-helix bundle domain (Figure S2).…”

Section: Resultsmentioning

confidence: 99%

Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori

Moonens

Gideonsson

Subedi

et al. 2016

Cell Host & Microbe

117

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Summary The Helicobacter pylori adhesin BabA binds mucosal ABO/Leb 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 Leb 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 Leb-expressing mice, providing perspectives on possible H. pylori eradication therapies.

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“…However, in ϳ20% of infected individuals it causes peptic ulcers, symptomatic gastritis, and/or gastric adenocarcinomas (12,13). H. pylori infection begins with colonization of the gastric epithelial lining, where the bacterium uses several adhesins, such as SabA or BabA, to anchor itself to a host gastric epithelial cell (14,15). A type four secretion system (T4SS) 2 comprised of ϳ30 proteins is then used by the bacterium to inject its sole effector protein, the oncoprotein CagA, into the host cell cytoplasm (16,17).…”

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confidence: 99%