The death receptor pathway as typified by Fas (CD95/APO-1). Oligomerization of Fas by FasL induces recruitment of FADD to the cytoplasmic tail of Fas by their mutual DDs (black boxes). The opposite end of FADD contains a death effector domain (DED; hatched boxes) that allows recruitment of either procaspase-8 or the related protein c-FLIP, which contains a sequence change in the sequence corresponding to the active site of procaspase-8 (black bar), rendering it enzymatically inactive. Caspase-8 can cleave the BH3-only protein Bid, and the resulting truncated Bid (tBid) can inactivate Bcl-2 in the mitochondrial membrane. This allows the escape of cytochrome c, which clusters with Apaf-1 and caspase-9 in the presence of dATP to activate caspase-9. Smac/DIABLO is also released from the mitochondria and inactivates inhibitors of apoptosis (IAPs). Active caspase-9 can cleave and activate procaspase-3 to its active form, leading to breakdown of several cytoskeletal proteins and degradation of the inhibitor of caspase-activated DNase (ICAD).