BCL-X(L) FORMS AN ION-CHANNEL IN SYNTHETIC LIPID-MEMBRANES

Bcl-2-related proteins are critical regulators of cell survival that a re localized to the outer mitochondrial, outer nuclear and endoplasmic reticulum membranes(1-4). Despite their physiological importance, the biochemical function of Bcl-2-related proteins has remained elusive. The three-dimensional structure of Bcl-x(L), an inhibitor of apoptosis , was recently shown to be similar to the structures of the pore-formi ng domains of bacterial toxins(5). A key feature of these pore-forming domains is the ability to form ion channels in biological membranes(6 ,7). Here we demonstrate that Bcl-x(L) shares this functional feature. Like the bacterial toxins, Bcl-X(L) can insert into either synthetic lipid vesicles or planar Lipid bilayers and form an ion-conducting cha nnel. This channel is pH-sensitive and becomes cation-selective at phy siological pH. The ion-conducting channel(s) formed by Bcl-x(L) displa y multiple conductance states that have identical ion selectivity. Tog ether, these data suggest that Bcl-x(L) may maintain cell survival by regulating the permeability of the intracellular membranes to which it is distributed.