Fas death domain

Signalling for apoptosis can involve a plasma Fas ligand which binds to the PM Fas receptor with resultant activation of an associated cytosol-side Fas death domain of Fas and activation of caspase 8. Caspase 8 is a thiol protease and once activated initiates a so-called caspase cascade leading to activation of further caspases (with consequent proteolysis) and activation of a DNase (leading to DNA destruction with formation of a characteristic DNA fragment ladder ). Caspase 8 acts on mitochondria with resultant release of cytochrome c, which promotes caspase 3 activation by caspase 8 and hence the caspase cascade . Another signalling pathway for apoptosis involves tumour necrosis factor (TNF) binding to the TNF receptor with consequent activation of a cytosolic-side TNF receptor-associated death domain (TRADD) and resultant activation of the caspase cascade and cell death. 

Structure of the death domain of Fas, consists of six amphipathic antiparallel a-hehces arranged in a unusual Greek Key topology (Huang et at, 1996) (Fig. IIA). The overall fold of other death domains, such as the NGFR p75 (Liepinsh et al., 1997), FADD (Jeong et al, 1999), and TNFR-1 (Sukits et al, 2001 Telliez et al, 2000) were found to be similar to the Fas death domain with only minor differences in the length and orientation for some of the a-helices (Fesik, 2000) (Fig. IIB). 

Boldin, M.P., Mett, I.L., Varfolomeev, E.E., Chumakov, 1., Shemer-Avni, Y., Camonis, J.H. and WaUach, D., 1995, Self-association of the death domain of the p55 tumor necrosis factor (TNF) receptor and Fas/APOl prompts signaling for TNF and Fas/APOl effects. J. Biol. Chem. 270 387-391... 

Chinnaiyan, A. M., O Rourke, K., Tewari, M., and Dixit, V. M., 1995, FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell SI 505-512. 

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). 

Fig. 5. A hypothetical model of the structure/function relationship between wild-type mFas and sFas variants. A requirement for the normal signahng process is to form homotrimers of the complete mFas molecules. sFas can also trimerize with wild-type mFas, suggesting that such an aberrant trimerization results in disruption of the signahng. Fas-L, Fas ligand DD, death domain aa, amino acid.

Thus, the KOB cells have been demonstrated ex vivo to prevent apoptosis by expression on their surfaces of function-ablating Fas antigen, which lacks the entire death domain. These aberrant Fas molecules probably behave as decoy receptors and interfere with the trimerization of normal Fas in a dominant negative manner, resulting in the impairment of signal transduction. 

Why missense mutations of the EC domain, except in the death domain, cause Fas-mediated signaling defects remains to be elucidated. We have established interesting ATL cell lines, designated S04 and RS04, that are instructive regarding... 

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). 

Binding of the ligand of the Fas receptor triggers clustering of the receptor and association of the cofactor FADD (fas-assodated protein with death domain) which interacts with the receptor via its death domain (DD). Procaspase 8 binds to FADD via a common DED (death effector domain) motif and is thereby also recruited into the Fas-receptor associated complex. Due to the clustering of the proteins, proximity-induced cleavage of procaspase 8 to the mature initiator caspase 8 takes place. This activates the effector caspases and triggers cell death. 

Stimulation of death receptors on the plasma membrane, such as TNF and Fas as well as DR3, DR4, and DR5, may be a trigger. The TNF receptor has an extracellular domain, a membrane-spanning domain, and an intracellular domain. The latter is also known as the death domain. 

FIGURE 12-50 Initial events of apoptosis. Receptors in the plasma membrane (Fas, TNF-R1) receive signals from outside the cell (the Fas ligand or tumor necrosis factor (TNF), respectively). Activated receptors foster interaction between the "death domain" (an 80 amino acid sequence) in Fas or TNF-R1 and a similar death domain in the cytosolic proteins FADD or TRADD. FADD activates a cytosolic protease, caspase 8, that proteolytically activates other cellular proteases. TRADD also activates proteases. The resulting proteolysis is a primary factor in cell death. 

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

The extrinsic pathway consists of a series of events initially induced by death receptors located on the cell surface. It is initiated by interaction of extracellular death ligands with their respective receptors, located on the surface of the plasma membrane. The death ligands are members of the tumor necrosis factor (TNF)/nerve growth factor (NGF) superfamily. TNF-R1, Fas (Apo-l/CD95), TRAIL-R1, TRAIL-R2, and NGF-R are examples of death receptors. They are transmembrane proteins consisting of an external domain, where the ligand associates, and a cytoplasmic domain, which contains the DD (death domain). 

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. 

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