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

Minn AJ, Kettlun CS, Liang H, Kelekar A, Vander Heiden MG, Chang BS, Fesik SW, Fill M, Thompson CB
EMBO J. 1999 18 (3): 632-43

PMID: 9927423 · PMCID: PMC1171156 · DOI:10.1093/emboj/18.3.632

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.

MeSH Terms (18)

Amino Acid Sequence Animals Apoptosis bcl-2-Associated X Protein bcl-X Protein Cell Line Cell Survival Dimerization Humans Ion Channels Mice Models, Molecular Molecular Sequence Data Protein Conformation Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Saccharomyces cerevisiae Transfection

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