## The Extrinsic Apoptotic Pathway **Key Point:** The extrinsic pathway is initiated by extracellular death signals (FasL, TNF-α, TRAIL) binding to death receptors on the cell surface, leading to rapid assembly of the death-inducing signaling complex (DISC) at the plasma membrane. ### DISC Assembly and Function 1. **Death receptor ligation**: FasL, TNF-α, or TRAIL binds to Fas, TNF-R1, or TRAIL-R (respectively). 2. **Recruitment of adaptor proteins**: Death receptors contain intracellular death domains (DD) that recruit FADD (Fas-associated protein with DD). 3. **DISC formation**: FADD recruits pro-caspase-8 (and pro-caspase-10) to form the DISC at the plasma membrane. 4. **Caspase-8 activation**: Proximity-induced autocleavage of pro-caspase-8 generates active caspase-8. 5. **Downstream effects**: - **Direct**: Caspase-8 cleaves executioner caspases (caspase-3, caspase-7) → apoptosis. - **Indirect**: Caspase-8 cleaves Bid (BH3-only protein) → tBid → mitochondrial pathway (intrinsic amplification). **High-Yield:** The DISC is a membrane-proximal complex; the apoptosome is a cytoplasmic complex. This distinction is critical for exam questions. ### Mnemonic: **DISC Components** **D**eath receptor → **I**ntracellular **S**ignaling **C**omplex - **D**eath receptor (Fas, TNF-R1, TRAIL-R) - **F**ADD (adaptor) - **P**ro-caspase-8 (initiator caspase) ### Comparison: DISC vs. Apoptosome | Feature | DISC | Apoptosome | |---------|------|------------| | **Location** | Plasma membrane | Cytoplasm | | **Pathway** | Extrinsic | Intrinsic | | **Key components** | Death receptor, FADD, pro-caspase-8 | Apaf-1, pro-caspase-9, cytochrome c | | **Trigger** | Death receptor ligation | Mitochondrial OMMP | | **Initiator caspase** | Caspase-8 | Caspase-9 | **Clinical Pearl:** Defects in DISC assembly (e.g., FADD mutations) impair extrinsic apoptosis and predispose to lymphoproliferative disorders and autoimmunity. 
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