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New Insights into the Mechanism of Permeation through Large Channels

Alexander G. Komarov ^* , Defeng Deng , William J. Craigen  and Marco Colombini ^*

^* Department of Biology, University of Maryland, College Park, Maryland 20742; Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine, Houston, Texas 77030; and St. Petersburg Nuclear Physics Institute, Gatchina, Russia, 188350

Correspondence: Address reprint requests to Marco Colombini, E-mail: colombin{at}umd.edu.

The mitochondrial channel, VDAC, regulates metabolite flux across the outer membrane. The open conformation has a higher conductance and anionic selectivity, whereas closed states prefer cations and exclude metabolites. In this study five mutations were introduced into mouse VDAC2 to neutralize the voltage sensor. Inserted into planar membranes, mutant channels lack voltage gating, have a lower conductance, demonstrate cationic selectivity, and, surprisingly, are still permeable to ATP. The estimated ATP flux through the mutant is comparable to that for wild-type VDAC2. The outer membranes of mitochondria containing the mutant are permeable to NADH and ADP/ATP. Both experiments support the counterintuitive conclusion that converting a channel from an anionic to a cationic preference does not substantially influence the flux of negatively charged metabolites. This finding supports our previous proposal that ATP translocation through VDAC is facilitated by a set of specific interactions between ATP and the channel wall.

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