Overview.
Apoptosis is a controlled process of programmed cell death, driven by a cascade of caspase activation to remove cells safely.
Initiator Caspases
- Initiator caspases are proteins that begin the apoptosis process.
- They are initially inactive monomers called procaspases.
- Each initiator procaspase has:
- A protease domain at the carboxy-terminal region.
- A small adaptor binding domain near the amino terminus.
- Apoptotic signals activate adaptor proteins with multiple binding sites for the caspase amino-terminal domain.
- Adaptor proteins bind to initiator procaspases and bring them together.
- This binding induces dimerization of initiator procaspases.
- Dimerization leads to cleavage at a specific site in the protease domains.
- Cleavage and rearrangement activate the initiator caspases.
- Each protease domain is rearranged into a large and a small subunit after activation.
Initiator Caspase Activation Summary Table
| Component | Initial State | Trigger/Interaction | Resulting Change |
|---|
| Initiator caspase | Inactive monomer (procaspase) | Binds adaptor proteins via amino-terminal domain | Dimerization and cleavage in protease domain |
| Adaptor protein | Inactive until apoptotic signal occurs | Receives apoptotic signal; exposes multiple binding sites | Recruits and clusters initiator procaspases |
| Protease domain | Single unit in procaspase | Cleaved at a specific site after dimerization | Rearranged into large and small subunits; becomes active |
Executioner Caspases
- Executioner caspases exist as dimers but are initially inactive.
- Initiator caspases activate executioner caspases by cleaving their protease domains.
- Cleavage causes a conformational change in the executioner caspase dimer.
- This conformational change converts executioner caspases into their active form.
- Active executioner caspases cleave many key cellular proteins.
- Protein cleavage leads to programmed death of the cell.
Executioner Caspase Activation Summary Table
| Step | State of Executioner Caspase | Action by Initiator Caspase | Outcome |
|---|
| Before activation | Inactive dimer | None | No proteolytic activity |
| Activation step | Dimer with intact protease domains | Cleavage within protease domains | Conformational change in the dimer |
| After activation | Active dimer | Previously cleaved and rearranged | Cleaves key proteins; drives cell apoptosis |
Overall Role of Apoptosis
- Apoptosis relies on a caspase cascade: initiator caspases activate executioner caspases.
- The controlled protein cleavage by executioner caspases ensures orderly cell dismantling.
- This process helps maintain tissue health by removing unnecessary or damaged cells.
Key Terms & Definitions
- Apoptosis: Controlled, programmed cell death that removes cells without causing damage to surrounding tissue.
- Initiator caspases: Caspases that first respond to apoptotic signals and activate executioner caspases.
- Executioner caspases: Caspases that directly cleave key cellular proteins to carry out cell death.
- Procaspase: Inactive precursor form of a caspase, often existing as a monomer before activation.
- Protease domain: Catalytic region of a caspase responsible for cutting target proteins.
- Adaptor proteins: Proteins that bind initiator procaspases and promote their dimerization and activation.
- Dimerization: Process where two monomeric proteins associate to form an active dimer.
- Conformational change: Structural rearrangement of a protein that alters its activity.
Action Items / Next Steps
- Review the sequence: apoptotic signal → adaptor activation → initiator caspase activation → executioner caspase activation.
- Practice drawing a simple flow diagram of initiator and executioner caspase activation steps.
- Memorize key terms: apoptosis, initiator caspase, executioner caspase, procaspase, adaptor protein.