Two remarkable serine/leucine polymorphisms in Helicobacter pylori: functional importance for serine protease HtrA and adhesin BabA

Abstract

Single nucleotide polymorphisms (SNPs) account for significant genomic variability in microbes, including the highly diverse gastric pathogen Helicobacter pylori. However, data on the effects of specific SNPs in pathogen-host interactions are scarce. Recent functional studies unravelled how a serine/leucine polymorphism in serine protease HtrA affects the formation of proteolytically active trimers and modulates cleavage of host cell-to-cell junction proteins during infection. A similar serine/leucine mutation in the carbohydrate binding domain of the adhesin BabA controls binding of ABO blood group antigens, enabling binding of either only the short Lewis b/H antigens of blood group O or also the larger antigens of blood groups A and B. Here we summarize the functional importance of these two remarkable bacterial SNPs and their effect on the outcome of pathogen-host interactions.

Keywords: Adaptation; BabA; Evolution; HtrA; SNP.

Fig. 1

SNPs in H. pylori HtrA and BabA and their effect on protein structure. A The disease-related SNP at HtrA position 171 in strains from patients with gastritis or gastric cancer and amino acids R32 and H46 involved in trimer formation. B Effect of the S171L exchange on the HtrA trimer interface. (left) Structure of trimeric HtrA (PDB:5Y28) as transparent surface representation. The three subunits shown as yellow, green, and pink ribbon. (middle) Enlargement of the trimer interface for the S171 variant. Residues S171, R32, and H46 are shown in space-filled presentation and are labelled. Subscript letters denote the origin from the three different subunits. (right) Same presentation for the trimer interface in the L171 variant. C BabA sequence diversity flanking the 198-199 signature position in selected generalist and specialist strains. D Structural features of BabA in generalist and specialist strains. (left) BabA from generalist strain 17875 in complex with blood group B Lewis b heptasaccharide BLe^b7 (PDB:5F7W). BLe^b7 is shown as space-filled presentation and BabA as transparent surface. The protein backbone is indicated by a white ribbon with the CL2 and DL1 loops in yellow and orange, respectively. (middle) BabA glycan binding site in the generalist strain 17875 highlighting the position of residues S198 and K199. (right) BabA glycan binding site in the specialist strain S831 (PDB: 5F8R). BLe^b7 was modelled into the glycan binding pocket to illustrate the steric overlap between the L198 sidechain and BLe^b7 (magenta arrow) that impedes binding of BLe^b7