title: New insights into the mechanism of permeation through large channels.
abstract: 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.
authors.affiliation: Department of Biology, University of Maryland, College Park, Maryland 20742, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Komarov
authors.forename: Defeng
authors.initials: D
authors.lastname: Deng
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: Marco
authors.initials: M
authors.lastname: Colombini
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002463:Cell Membrane Permeability / Q000502:physiology*; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D009243:NAD / Q000378:metabolism*; D016062:Porosity; D011485:Protein Binding; D050996:Voltage-Dependent Anion Channel 2 / Q000378:metabolism*
chemical_list: C494766:Vdac2 protein, mouse; D050996:Voltage-Dependent Anion Channel 2; D009243:NAD; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate