Fas-associated death domains

An important trigger for apoptosis is known as the Fas system. This is used by cytotoxic Tcells, for example, which eliminate infected cells in this way (top left). Most of the body s cells have Fas receptors (CD 95) on their plasma membrane. If a T cell is activated by contact with an MHC presenting a viral peptide (see p. 296), binding of its Fas ligands occurs on the target cell s Fas receptors. Via the mediator protein FADD ( Fas-associated death domain ), this activates cas-pase-8 inside the cell, setting in motion the apoptotic process. 

VIO. Vincenz, C., and Dixit, V. M., Fas-associated death domain protein interleukin-1 betaconverting enzyme 2 (ET.1CE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. J. Biol. Chem. Ill, 6578-6583 (1997). 

In the case of the death receptor Fas (see 15.4), activation of the caspase involves a protein that interacts with the cytoplasmic part of the receptor and is known as FADD protein (Fas-associated death domain). The FADD protein has distinct structural motives that mediate specific interactions with other proteins. It interacts via the death domain with the receptor and via the death effector domain with the corresponding caspase (here caspase 8). 

FADD Fas-associated death domain, an adapter protein... 

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. 

TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF TNF-Rl and TNF-R2. The binding of TNF to TNF-Rl has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain (FADD). The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially autoimmune diseases (see Chapter 15). 

A similar process occurs for caspase-8 activation. In this case, oligomerization of the death adaptor protein Fas-Associated Death Domain (FADD) recruits procaspase-8 into the death-inducing signalling complex (DISC) allowing caspase-8 dimerization and subsequent activation (Shi, 2006). 

Rosenthal, D.S., Velena, A. et al. (2003). Expression of dominantnegative Fas-associated death domain blocks human kerati-noc 4e apoptosis and vesication induced by sulfur mustard. J. Biol. Chem. 278 8531 0. 

Thorburn J, et al. Selective inactivation of a Fas-associated death domain protein (FADD)-dependent apoptosis and autophagy pathway in immortal epithelial cells. Mol. Biol. Cell 2005 16 1189-1199. 

Fig. 3. Schematic representation of extrinsic cell death signaling mediated by Fas ligand (FasL). Binding of FasL to Fas receptor initiates cytosolic aggregation of multiple death domains (e.g. Fas-associated death domains (FADDs)), initiating caspase activation, and subsequent apoptotic death of the cell.

Buechler C, Bared SM, Aslanidis C, et al. (2002a) Molecular and functional interaction of the ATP-binding cassette transporter Al with Fas-associated death domain protein. I Biol Chem 277 41307-41310... 

Death domain receptors. The cytokine TNF (tumor necrosis factor) uses a type of receptor called the death domain receptor (Fig. 11.21). These receptors function as a trimer when they bind TNF (which is also a trimer). On TNF binding, an inhibitory protein called the silencer of death is released from the receptor. The receptor then binds and activates several adaptor proteins. One adaptor protein, FADD (fas-associated death domain), recruits and activates the zymogen form of a proteolytic enzyme called caspase. Caspases... 

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