Molecular structure of VacA. (A) The p55 domain of VacA adopts a β-helix structure that is composed of three parallel β-sheets connected by loops of varying length and structure [51]. The carboxy-terminal domain contains a mixture of α/β secondary structure elements and contains a disulfide bond. The carboxy-terminus of the β-helix (right, rotated by 90°) is capped by a β-hairpin from the carboxy-terminal domain and the α1−helix located in one of the long helix loops. (B) Docking the p55 crystal structure into a 19-Å cryo electron microscopy map of the VacA dodecamer results in a model for oligomerization. Twelve p55 subunits are shown docked into a 19-Å cryo-EM map of a VacA dodecamer [44]. An arrow is shown to indicate the space that the upper molecule will occupy if p33 extends the β-helix structure of p55. The inset shows EM images of a VacA hexamer and a VacA monomer [44]. The shape of a VacA hexamer (inset) is similar to the shape of a single layer within the dodecamer [44]. The rod-like shape of the p88 monomer (inset) supports a model in which the β-helix of p55 will extend into p33. (C) The view from the left structure in panel B is rotated by 90°. This figure was kindly provided by Dr. Borden Lacy and originally published by Gangwer et al. [51] with kind permission of the National Academy of Sciences, USA.

VacA domain structure and processing products. The amino-terminal signal sequence (SS) and carboxy-terminal domain are cleaved from the full-length 135-140 kDa VacA protein to yield a 98 kDa secreted toxin (p98) that is transported into the extracellular space via the autotransporter mechanism. Proteins of this autotransporter family are able to mediate their own secretion without the need of additional bacterial proteins. The 33 kDa carboxy-terminal beta-barrel domain of VacA is predicted to insert into the outer membrane and to form a channel, through which the mature VacA toxin is secreted. The secreted toxin can be processed into the mature toxin (p88) and p10. The mature, secreted p88 subunit can undergo further limited proteolytic cleavage to yield two additional fragments, p33 and p55 [7,8,32]. The latter two processing products are considered to represent the functional domains or subunits of VacA.

Model of the various activities of VacA to induce altered host cell signalling in epithelial and immune cells which contributes to persitent Hp colonization in the human stomach.