Bcl-x(L) regulates apoptosis by heterodimerization-dependent and -independent mechanisms

Andy J. Minn, Claudia S. Kettlun, Heng Liang, Ameeta Kelekar, Matthew G. Vander Heiden, Brian S. Chang, Steven W. Fesik, Michael Fill, Craig B. Thompson

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A hydrophobic cleft formed by the BH1, BH2 and BH3 domains of Bcl-x(L) is responsible for interactions between Bcl-x(L) and BH3-containing death agonists. Mutants were constructed which did not bind to Bax but retained anti-apoptotic activity. Since Bcl-x(L) 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-x(L) through heterodimerization-dependent and -independent mechanisms. These data suggest that Bcl-x(L) 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.

Original languageEnglish (US)
Pages (from-to)632-643
Number of pages12
JournalEMBO Journal
Issue number3
StatePublished - Feb 1 1999


  • Apoptosis
  • Bax
  • Bcl-x(L)
  • Ion channel
  • Yeast


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