Apoptosis
APOPTOSIS
- Programmed cell death
- Specific biochemical signature (ex. phosphatidylserine "flips" to outer surface of plasma membrane)
- Does not induce inflammation
Important in a Variety of Processes
- Organism development
- Cell number and organ size
- Quality control during development
- Removal of damaged cells
Cellular Changes
- Cytoplasm condenses
- Nucleus becomes misshapen
- Chromatin condenses along the nuclear envelope
- Cell eventually fragments into blebs
- Phosphatidylserine on the blebs indicates to phagocytic cells that apoptosis is occurring
- Phagocytic cells clear the cellular debris
Two Paths of Apoptosis
1) Extrinsic Pathway (using the Fas pathway as an example)
a) Trimeric Fas ligand on another cell binds to Fas death receptor
b) Intracellular domain of Fas receptor recruits and activates FADD (Fas associated death domain)
c) Activated FADD recruits initiator procaspases such as procaspase-8 or -10 (complex is referred to as death-inducing signaling complex or DISC)
d) Complex formation activates the procaspases which then activate executioner caspases
e) Executioner caspase activation leads to apoptosis
2) Intrinsic Pathway
a) Apoptotic stimulus activates BH3-only protein
b) BH3-only protein blocks the activity of Bcl-2 protein
c) Without Bcl-2 activity, BH123 proteins are able to oligomerize and cytochrome c is released from the intermembrane space of mitochondria
d) Cytochrome c in the cytoplasm activates Apaf1 proteins which form a heptameric complex
e) Apaf1 complex recruits initiator procaspase-9
f) Activated caspase-9 activates executioner caspase
g) Executioner caspase activation leads to apoptosis
Bcl-2 Family of Proteins
- Based on which specific domains are present in the protein