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Biophys J, December 2001, p. 3204-3215, Vol. 81, No. 6

How the Loop and Middle Regions Influence the Properties of Helicobacter pylori VacA Channels

Francesco Tombola,* Cristina Pagliaccia,dagger Silvia Campello,* John L. Telford,dagger Cesare Montecucco,* Emanuele Papini,Dagger and Mario Zoratti*

 *Centro Biomembrane del Consiglia Nazionale delle Ricerche and Dipartimento di Scienze Biomediche, Università di Padova, Italy;  dagger Istituto Ricerche Immunologicae Siena, CHIRON S.p.A., Siena, Italy;  Dagger Dipartimento di Scienze Biomediche e Oncologia Umana, Sezione di Patologia Generale, Università di Bari, Italy

VacA is a pore-forming cytotoxin produced by Helicobacter pylori in several strain-specific isoforms, which have been classified in two main families, m1 and m2, according to the sequence of a variable "midregion." Both forms are associated with gastric pathologies and can induce vacuolation of cultured cells. The comparison of two representative toxins, m1 17874 and m2 9554, has indicated that the m2 form is less powerful in vacuolation assays and that its effects are more strongly cell type dependent. To rationalize these differences and to investigate structure-function relationships in this toxin, we have compared the properties of the channels formed by these two variants and by a construct derived from 17874 by deleting a loop that connects the two toxin domains, which is shorter in 9554 than in 17874. Although the channels formed by all three proteins are similar, m2 9554 channels have, on average, a lower conductance and are less anion-selective and more voltage-dependent than the m1 pores. Furthermore, the rate of incorporation of 9554 VacA into planar bilayers depends on lipid composition much more strongly than that of 17874. The comparison with the behavior of the loop deletion mutant indicates that this latter property, as well as a portion of the conductance decrease, may be attributed to the reduction in loop length. The differences in pore properties are proposed to account in part for the different cytotoxicity exhibited by the two toxin isoforms. We furthermore present evidence suggesting that the conformation of the membrane-embedded toxin may be influenced by the lipid composition of the membrane itself.

Biophys J, December 2001, p. 3204-3215, Vol. 81, No. 6
© 2001 by the Biophysical Society   0006-3495/01/12/3204/12  $2.00


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Fluorescence Resonance Energy Transfer Microscopy of the Helicobacter pylori Vacuolating Cytotoxin within Mammalian Cells
Infect. Immun., July 1, 2002; 70(7): 3824 - 3832.
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