title: Bcl-x(L) forms an ion channel in synthetic lipid membranes.
abstract: Bcl-2-related proteins are critical regulators of cell survival that are localized to the outer mitochondrial, outer nuclear and endoplasmic reticulum membranes. Despite their physiological importance, the biochemical function of Bcl-2-related proteins has remained elusive. The three-dimensional structure of Bcl-xL, an inhibitor of apoptosis, was recently shown to be similar to the structures of the pore-forming domains of bacterial toxins. A key feature of these pore-forming domains is the ability to form ion channels in biological membranes. Here we demonstrate that Bcl-xL shares this functional feature. Like the bacterial toxins, Bcl-xL can insert into either synthetic lipid vesicles or planar lipid bilayers and form an ion-conducting channel. This channel is pH-sensitive and becomes cation-selective at physiological pH. The ion-conducting channel(s) formed by Bcl-xL display multiple conductance states that have identical ion selectivity. Together, these data suggest that Bcl-xL may maintain cell survival by regulating the permeability of the intracellular membranes to which it is distributed.
authors.affiliation: Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Illinois 60637, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Minn
authors.forename: P
authors.initials: P
authors.lastname: Vélez
authors.forename: S L
authors.initials: SL
authors.lastname: Schendel
authors.forename: H
authors.initials: H
authors.lastname: Liang
authors.forename: S W
authors.initials: SW
authors.lastname: Muchmore
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
authors.forename: M
authors.initials: M
authors.lastname: Fill
authors.forename: C B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D002412:Cations / Q000378:metabolism; D002463:Cell Membrane Permeability; D004563:Electrochemistry; D004926:Escherichia coli; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008051:Lipid Bilayers; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D002412:Cations; D007473:Ion Channels; D008051:Lipid Bilayers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein