Bcl-xL regulates apoptosis by heterodimerization-dependent and -independent mechanisms

Open Access
Publisher Website
Google Scholar
Abstract
A hydrophobic cleft formed by the BH1, BH2 and BH3 domains of Bcl‐xL is responsible for interactions between Bcl‐xL and BH3‐containing death agonists. Mutants were constructed which did not bind to Bax but retained anti‐apoptotic activity. Since Bcl‐xL can form an ion channel in synthetic lipid membranes, the possibility that this property has a role in heterodimerization‐independent cell survival was tested by replacing amino acids within the predicted channel‐forming domain with the corresponding amino acids from Bax. The resulting chimera showed a reduced ability to adopt an open conductance state over a wide range of membrane potentials. Although this construct retained the ability to heterodimerize with Bax and to inhibit apoptosis, when a mutation was introduced that rendered the chimera incapable of heterodimerization, the resulting protein failed to prevent both apoptosis in mammalian cells and Bax‐mediated growth defect in yeast. Similar to mammalian cells undergoing apoptosis, yeast cells expressing Bax exhibited changes in mitochondrial properties that were inhibited by Bcl‐xL through heterodimerization‐dependent and ‐independent mechanisms. These data suggest that Bcl‐xL regulates cell survival by at least two distinct mechanisms; one is associated with heterodimerization and the other with the ability to form a sustained ion channel.