Protein Domain : Vacuolating cytotoxin IPR003842

Type	Family
Description	Helicobacter pylori is a micro-aerophilic bacterium with the extraordinary ability to establish infections in human stomachs that can last for years or decades, despite immune and inflammatory responses and normal turnover of the gastric epithelium and overlying mucin layer in which it resides. Most H. pylori strains secrete a toxin (VacA) that induces multiple structural and functional alterations in eukaryotic cells. The most prominent effect of VacA is its capacity to induce the formation of largecytoplasmic vacuoles in eukaryotic cells. In addition, VacA interferes with the process of antigen presentation, increases permeability of polarised epithelial cell monolayers, and forms anion-selective membrane channels. Formation of channels in endosomal membranes of cells may be an important feature of the mechanism by which VacA induces cell vacuolation. H. pylori vacA encodes a ~139kDa protoxin, which undergoes cleavage of a 33-residue N-terminal signal sequence and C-terminal proteolytic processing to yield a mature secreted toxin. Purified VacA degrades during prolonged storage into two fragments (of ~34 and 58kDa), which are derived from theN- and the C terminus of the toxin respectively. The mass of the experimentally intact toxin (~88.2kDa) corresponds closely to the sum of the masses of the two proteolytic fragments [ ].Secondary structure predictions suggest that a 35kDa portion of the VacA C-terminal domain is rich in amphipathic β-sheets, and this region exhibits low-level similarity to members of the family of autotransporter proteins. In addition, at the C terminus of VacA, there is a phenylalanine- containing motif that is commonly found in autotransporter proteins, as wellas in numerous Gram-negative bacterial outer membrane proteins. An intact N-terminal portion of VacA is not required for proteolytic processing of theprotoxin. However, the N-terminal 32 amino acids of the mature VacA are predicted to form the only contiguous hydrophobic region in the protein thatis long enough to span the membrane. What is more, isogenic H. pylori mutant strains in which the C-terminal VacA domain is disrupted, fail to express orsecrete any detectable VacA, which is probably attributable to the degradation of export-incompetent toxin precursors within the periplasm. It is speculated that the VacA protoxin may undergo proteolytic cleavage at multiple sites downstream from amino acid 854 of the protoxin, which wouldyield a 33kDa cell-associated domain, as well as a fragment of ~15kDa [ ].
Short Name	Vacuolating_cytotoxin