Death receptor complex

Antonsson and Marinou 2000 Adams and Cory, 1998). Stress may also cause inaease, nitric oxide (NO), or reactive oxygen species (ROS) production which, in turn, triggers release of apoptotic proteins from the intermemhrane space (Kroemer and Reed, 2000 Vieira et at, 2000). Release of these proteins from mitochondria are required for stress induced killing hut are, with a few exceptions (Bergmann et al, 1994, Schulze- Osthoff et al, 1993), dispensible for CD95 and TNF-receptor transduced apoptosis. These other death processes require FADD and caspase-8 to be recruited into the death receptor complexes and cannot be blocked by Bcl-2 (Krammer, 2000 Scaffidi et al, 1998). 

A link between the pathways controlled by the TNF-receptor family members and the mitochondrial pathway has been identified. It has been shown that caspase-8 can cleave Bid, resulting in the formation of truncated Bid (tBid), a death-inducing member of the Bcl-2 family (Gross et al, 1999 Li et al, 1998 Luo et al., 1998). Bid activation appears not to be essential in cells with high amoimts of caspase-8 in the death receptor complex but may be required to amplify the cascade in cells with low amounts of caspase-8 in the death receptor complex. 

Some cell types maintain a low level of caspase 8 in the cytoplasm. Therefore, in the presence of apoptotic stimuli, this small amount of caspase 8 is activated in the DISC complex, and the subsequent activation of effector caspases is not possible. These cell types are called type II and also require the mitochondrial pathway activation. These two pathways can communicate through the cleavage of a Bcl-2 member, Bid, by caspase 8 (Li et al., 1998). Cell lines that have a higher level of caspase 8 in the cytoplasm are called type I. In these cells, Bcl-2 family members do not regulate the death receptor-mediated pathway. 

Extrinsic (death receptor) pathway of caspase activation during apoptosis involves the binding of death ligands to cell surface receptors (e.g., Fas/ CD95/Apo-l or TNF receptor), recruitment of adaptor molecules Fas-associated death domain (FADD) or TNF receptor-associated death domain (TRADD) to the cytosolic end of the receptor, and formation of the death-inducing signaling complex (DISC) at the plasma membrane. DISC recruits and activates the initiator caspases, caspase-8 or -10. 

The mechanisms of apoptosis are highly complex and sophisticated, involving an energy-dependent cascade of molecular events (Figure 16.11). There are two main apoptotic pathways the extrinsic or death receptor pathway and the intrinsic or... 

While the current structural and functional studies have shed lights on the molecular mechanisms of post-receptor signal transduction by the TNFR superfamUy, many important questions remain. One such question is the structural basis for the formation of death receptor signaling complexes, involving DD-DD and DED-DED interactions. Another question is the molecular basis of TRAP downstream signaling. Does it involve oligomerization and proximity induced activation of down-stream effectors, or conformational modulations Because of the importance of the TNFR superfamily in human disease, an ultimate question lies on the translation of structural and functional studies into therapeutic applications. 

It is worth mentioning that in death receptor-mediated apoptosis, cells can be divided into two groups depending on the requirement for mitochondria to induce a complete apoptotic response. Type I cells do not require the mitochondrial pathway because the recruitment of procaspase-8 into the DISC complex is enough to fully activate caspase-8 which then activates effector caspases. However, Type II cells are characterized by an incomplete apoptotic response unless mitochondria are involved (Scaffidi et al., 1999). In this type of cell, efficient activation of effector caspases requires the mitochondrial amplification loop (Fig. 5). Caspase-8 cleaves cytosolic Bid, a BH3-only protein, which when cleaved to tBid is able to translocate to the mitochondria and trigger release of the proapoptotic factors cytochrome c and Smac/DIABLO (Li et al., 1998 Deng et al., 2002). The release of cytochrome c triggers apoptosome formation, subsequent caspase-9 activation, and finally the activation of effector caspases such as caspase-3. 

Like other receptors, death receptors are activated by binding ligands. The activated death receptor-ligand complex is linked with its death domain (DD) to a homologous DED (death effector region), repeated in tandem, and recruits a zymogen form of a protease, pro-caspase 8 (Fig. 13.1). But the linker is, like other linkers, versatile. 

Rg. 13.1 The CD95-liganded death receptor with the intracellular death domains (DDs) binds to the death effector domain (DED) which links the receptor-ligand complex to the procaspase 8. Cell denotes the cell boundary. (Based on the information in Rg. 1 of ref. 5 and reproduced with permission of the authors and Science.)... 

Tumor necrosis factor receptor-associated protein with death domain, an adapter protein that recruits other proteins to the cytoplasmic TNF (tumor necrosis factor) receptor complex, involved in apoptosis... 

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