Mitochondrial permeabilization relies on BH3 ligands engaging multiple prosurvival Bcl-2 relatives, not Bak
Details
Publication Year 2007-04-23, Volume 177, Issue #2, Page 277-287
Journal Title
JOURNAL OF CELL BIOLOGY
Publication Type
Journal Article
Abstract
The Bcl-2 family regulates apoptosis by controlling mitochondrial integrity. To clarify whether its prosurvival members function by sequestering their Bcl-2 homology 3 (BH3)-only ligands or their multidomain relatives Bak and Bax, we analyzed whether four prosurvival proteins differing in their ability to bind specific BH3 peptides or Bak could protect isolated mitochondria. Most BH3 peptides could induce temperature-dependent cytochrome c release, but permeabilization was prevented by Bcl-x(L), Bcl-w, Mcl-1, or BHRF1. However, their protection correlated with the ability to bind Bak rather than the added BH3 peptide and could be overcome only by BH3 peptides that bind directly to the appropriate prosurvival member. Mitochondria protected by both Bcl-x(L)-like and Mcl-1 proteins were disrupted only by BH3 peptides that engage both. BH3-only reagents freed Bak from Bcl-x(L) and Mcl-1 in mitochondrial and cell lysates. The findings support a model for the control of apoptosis in which certain prosurvival proteins sequester Bak/Bax, and BH3-only proteins must neutralize all protective prosurvival proteins to allow Bak/Bax to induce mitochondrial disruption.
Publisher
ROCKEFELLER UNIV PRESS
Keywords
PRO-APOPTOTIC PROTEINS; CYTOCHROME-C RELEASE; BH3-ONLY PROTEINS; FAMILY-MEMBERS; CELL-DEATH; MEMBRANE; MCL-1; LIFE; REGULATORS; BCL-X(L)
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2007-04-23 12:00:00
Last Modified: 0001-01-01 12:00:00
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