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Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex
1Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Abstract:
Genetic analysis of apoptosis in the nematode Caenorhabditis elegans has revealed the cell death machine to be composed of three core interacting components. CED-4 (equivalent to mammalian Apaf-1) is a nucleotide binding molecule that complexes with the zymogen form of the death protease CED-3, leading to its autoactivation and cell death. CED-9 blocks death by complexing with CED-4 and attenuating its ability to promote CED-3 activation. An equivalent ternary complex was found to be present in mammalian cells involving Apaf-1, the mammalian death protease caspase-9, and Bcl-XL, an anti-apoptotic member of the Bcl-2 family. Consistent with a central role for caspase-9, a dominant negative form effectively inhibited cell death initiated by a wide variety of inducers.
Insights
The apoptosis cell death pathway involves three core components. A conserved mechanism exists in both nematodes and mammals, highlighting the role of caspase-9 in initiating cell death.
Area of Science:
- Cell biology
- Genetics
- Molecular biology
Background:
- Apoptosis, or programmed cell death, is crucial for development and tissue homeostasis.
- Understanding the molecular machinery of apoptosis is key to deciphering its role in disease.
Purpose of the Study:
- To elucidate the core components and interactions of the apoptosis pathway.
- To investigate the conservation of apoptotic mechanisms between nematodes and mammals.
Main Methods:
- Genetic analysis in Caenorhabditis elegans.
- Biochemical complex formation studies.
- Inhibition studies using dominant-negative caspase-9.
Main Results:
- Identified CED-4, CED-3, and CED-9 as core interacting components in C. elegans apoptosis.
- Demonstrated a conserved ternary complex in mammalian cells involving Apaf-1, caspase-9, and Bcl-XL.
- Showed that dominant-negative caspase-9 inhibits various cell death inducers.
Conclusions:
- The apoptosis machinery is conserved across species, with key proteins like Apaf-1 and caspase-9 playing central roles.
- CED-4 and Apaf-1 are functionally equivalent, as are CED-3 and caspase-9.
- CED-9 and Bcl-XL act as negative regulators by interacting with CED-4/Apaf-1.