Mimicry of a host anion channel by a Helicobacter pylori pore-forming toxin |
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Authors: | Czajkowsky Daniel M Iwamoto Hideki Szabo Gabor Cover Timothy L Shao Zhifeng |
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Affiliation: | * Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 † Department of Pharmacology, University School of Medicine and Veterans Affairs Medical Center, Nashville, Tennessee 37232 ‡ Departments of Medicine and Microbiology and Immunology, Vanderbilt University School of Medicine and Veterans Affairs Medical Center, Nashville, Tennessee 37232 |
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Abstract: | Bacterial pore-forming toxins have traditionally been thought to function either by causing an essentially unrestricted flux of ions and molecules across a membrane or by effecting the transmembrane transport of an enzymatically active bacterial peptide. However, the Helicobacter pylori pore-forming toxin, VacA, does not appear to function by either of these mechanisms, even though at least some of its effects in cells are dependent on its pore-forming ability. Here we show that the VacA channel exhibits two of the most characteristic electrophysiological properties of a specific family of cellular channels, the ClC channels: an open probability dependent on the molar ratio of permeable ions and single channel events resolvable as two independent, voltage-dependent transitions. The sharing of such peculiar properties by VacA and host ClC channels, together with their similar magnitudes of conductance, ion selectivities, and localization within eukaryotic cells, suggests a novel mechanism of toxin action in which the VacA pore largely mimics the electrophysiological behavior of a host channel, differing only in the membrane potential at which it closes. As a result, VacA can perturb, but not necessarily abolish, the homeostatic ionic imbalance across a membrane and so change cellular physiology without necessarily jeopardizing vitality. |
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