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BCL-2 Selectively Interacts with the BID-induced Open Conformer of BAK, Inhibiting BAK Auto-oligomerization
- Source :
- Journal of Biological Chemistry. 278:25039-25045
- Publication Year :
- 2003
- Publisher :
- Elsevier BV, 2003.
-
Abstract
- Caspase-8 cleaves BID to tBID, which targets mitochondria and induces oligomerization of BAX and BAK within the outer membrane, resulting in release of cytochrome c from the organelle. Here, we have initiated these steps in isolated mitochondria derived from control and BCL-2-overexpressing cells using synthetic BH3 peptides and subsequently analyzed the BCL members by chemical cross-linking. The results show that the BH3 domain of BID interacts with and induces an "open" conformation of BAK, exposing the BAK N terminus. This open (activated) conformer of BAK potently induces oligomerization of non-activated ("closed") conformers, causing a cascade of BAK auto-oligomerization. Induction of the open conformation of BAK occurs even in the presence of excess BCL-2, but BCL-2 selectively interacts with this open conformer and blocks BAK oligomerization and cytochrome c release, dependent on the ratio of BID BH3 and BCL-2. This mechanism of inhibition by BCL-2 also occurs in intact cells stimulated with Fas or expressing tBID. Although BID BH3 interacts with both BCL-2 and BAK, the results indicate that when BCL-2 is in excess it can sequester the BID BH3-induced activated conformer of BAK, effectively blocking downstream events. This model suggests that the primary mechanism for BCL-2 blockade targets activated BAK rather than sequestering tBID.
- Subjects :
- Protein Conformation
Molecular Sequence Data
Apoptosis
Plasma protein binding
Mitochondrion
Biochemistry
Protein structure
Amino Acid Sequence
Molecular Biology
biology
Chemistry
Cytochrome c
Membrane Proteins
Cell Biology
Cell biology
N-terminus
bcl-2 Homologous Antagonist-Killer Protein
Proto-Oncogene Proteins c-bcl-2
biology.protein
biological phenomena, cell phenomena, and immunity
Carrier Proteins
Bacterial outer membrane
Dimerization
Bcl-2 Homologous Antagonist-Killer Protein
BH3 Interacting Domain Death Agonist Protein
Protein Binding
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 278
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....c066ed9602adffe41e350b7190c21bde
- Full Text :
- https://doi.org/10.1074/jbc.m302930200