Death-inducing signaling complex DISC

Medema, J. P., Scaffidi, C., Kischkel, F. C., Shevchenko, A., Mann, M., Krammer, P. H., and Peter, M. E., 1997, FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). Embo J 16 2794-2804. 

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. 

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). 

Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME. Cytotoxicity-dependent APO-1 (Eas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EM BO J1995 14 5579-5588. 

The TRADD or FADD domains bind to adapter proteins in the cytosol and together they form of a death inducing signaling complex (DISC). This complex recruits caspase-8, one of a family of calcium ion-activated serine proteases (caspases) which cleave polypeptides on the C-terminal side of their aspartate residues. DISC activates caspase-8 to activate a Bcl-2 activator, BID (Fig. 13.1 Oa). The resultant tBid fragment activates effector Bcl-2 proteins on the endoplasmic reticular membrane and mitochondrial outer membrane. 

At present, there are two relatively well-characterized cell death pathways that result in the activation of executioner caspases (Figure 2). One is receptor-mediated and the other is mitochondrial-dependent. On receiving an apoptotic stimulus, the receptor-depen-dent pathway is initiated by activation of cell death receptors such as Fas and tumor necrosis factor. The death receptor stimulation results in the formation of a death inducing signaling complex (DISC) that recruits and activates procaspase-8, which in turn cleaves and... 

It is one of many proteins involved in apoptosis whose sfructures are known. The FADD molecule contains a death effector domain (DED), which associates with a similar domain in the proenzyme procaspase 8. A rather large membrane-associated molecular complex, the death-inducing signaling complex (DISC Fig. 32-4), is assembled in this... 

The Fas receptor (CD95) binds the Fas ligand (FasL), a transmembrane protein part of TNF family. The interaction between Fas and FasL results in the formation of death-inducing signaling complex (DISC), which contains the FADD., caspase-8, and caspase-10. In some types of cells, processed caspase-8 directly activates other members of the caspase family and triggers the execution of apoptosis of the cell. In other types of cells (type II), the Fas-DISC triggers the release of proapoptotic factors from mitochondria and the amplified activation of caspase-8 [24]. 

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