OLIGOMERIC AND SUBUNIT STRUCTURE OF THE HELICOBACTER-PYLORI VACUOLATING CYTOTOXIN

Disease-associated strains of Helicobacter pylori produce a potent tox in that is believed to play a key role in peptic ulcer disease in man. In vitro the toxin causes severe vacuolar degeneration in target cell s and has thus been termed VacA (for vacuolating cytotoxin A). Cytotox ic activity is associated with a >600-kD protein consisting of several copies of a 95-kD polypeptide that undergoes specific proteolytic cle avage after release from the bacteria to produce 37- and 58-kD fragmen ts. Quick freeze, deep etch electron microscopy has revealed that the native cytotoxin is formed as regular oligomers with either six- or se ven-fold radial symmetry. Within each monomer, two domains can clearly be distinguished, suggesting that the 37- and 58-kD fragments derive from proteolytic cleavage between discrete subunits of the monomer. An alysis of preparations of the toxin that had undergone extensive cleav age into the 37- and 58-kD subunits supports this interpretation and r eveals that after cleavage the subunits remain associated in the oligo meric structure, The data suggest a structural similarity with AB-type toxins.