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- Title
Bcl-x<sub>L</sub> regulates apoptosis by heterodimerization-dependent and -independent mechanisms.
- Authors
Minn, Andy J.; Kettlun, Claudia S.; Heng Liang; Kelekar, Ameeta; Heiden, Matthew G. Vander; Chang, Brian S.; Fesik, Steven W.; Fill, Michael; Thompson, Craig B.
- 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.
- Subjects
HYDROPHOBIC surfaces; GENETIC mutation; ION channels; AMINO acids; APOPTOSIS; CELL membranes
- Publication
EMBO Journal, 1999, Vol 18, Issue 3, p632
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/18.3.632