Figure 4. Model of DISC formation: mechanism of receptor signaling through clustering.

Schematic illustrating DISC formation. a, Model for Fas opening. Like in any two state model, it can be assumed that the closed and open form of Fas exist in equilibrium. In the absence of an apoptotic signal the equilibrium between closed and open forms of Fas strongly favors the closed form while open forms are unstable. Upon an apoptotic stimulus the equilibrium shifts to favor the open form of Fas. Fas molecules are brought together by Fas ligand in a permissive environment dependent on several factors including lipid rafts and membrane constitution. The close proximity of Fas DDs now allows for stem helices to interact leading to stabilization of the open form. b, Opening and formation of the Fas/Fas bridge links trimeric DD units defined in earlier studies (Supplementary Table 2), which are formed by globular regions of the open Fas. FADD can now bind to the open Fas molecules further stabilizing the bridge. The consequence is processive interlinked DISC formation and clustering in which open Fas molecules interacting via their globular domains are linked by a multitude of weak Fas/FADD bridges leading to overall stable DISC clusters. This permits activation of caspase-8, presumable by proximity enforced dimerization³⁰, and induction of Apoptosis.