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Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane
R Eskes1, S Desagher, B Antonsson
1Serono Pharmaceutical Research Institute, Ares Serono International S.A., CH-1228 Plan-les Ouates, Geneva, Switzerland.
Abstract:
In many types of apoptosis, the proapoptotic protein Bax undergoes a change in conformation at the level of the mitochondria. This event always precedes the release of mitochondrial cytochrome c, which, in the cytosol, activates caspases through binding to Apaf-1. The mechanisms by which Bax triggers cytochrome c release are unknown. Here we show that following binding to the BH3-domain-only proapoptotic protein Bid, Bax oligomerizes and then integrates in the outer mitochondrial membrane, where it triggers cytochrome c release. Bax mitochondrial membrane insertion triggered by Bid may represent a key step in pathways leading to apoptosis.
Insights
The proapoptotic protein Bax changes shape at mitochondria, then triggers cytochrome c release. This Bax mitochondrial membrane insertion, activated by Bid, is a key step in programmed cell death (apoptosis).
Area of Science:
- Cell biology
- Molecular biology
- Biochemistry
Background:
- Apoptosis is a crucial process for multicellular organisms.
- The protein Bax plays a key role in initiating apoptosis.
- Bax conformational changes at mitochondria precede cytochrome c release, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Bax triggers cytochrome c release from mitochondria.
- To investigate the role of the BH3-domain-only protein Bid in Bax activation.
Main Methods:
- Mitochondrial isolation and biochemical assays.
- Protein-protein interaction studies.
- Analysis of Bax oligomerization and membrane integration.
Main Results:
- Bax undergoes conformational changes and oligomerizes upon binding to Bid.
- Oligomerized Bax integrates into the outer mitochondrial membrane.
- Bax integration into the outer mitochondrial membrane directly triggers cytochrome c release.
Conclusions:
- Bid-induced Bax mitochondrial membrane insertion is a critical event in the intrinsic apoptosis pathway.
- This mechanism explains how Bax initiates cytochrome c release, activating downstream caspases.
- Targeting Bax-Bid interaction could be a therapeutic strategy for apoptosis-related diseases.