The Fas/FADD death domain complex structure unravels signaling by receptor clustering

The Death Inducing Signaling Complex (DISC) formed by Fas receptor, FADD and caspase-8 is a pivotal trigger of apoptosis1-3. The Fas/FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains (DD) of Fas and FADD is at the center of DISC formation4, 5. Thus characterising the mechanistic basis for the Fas/FADD interaction is paramount for understanding DISC signaling but has remained enigmatic largely due to a lack of structural data. We have successfully formed and isolated the Fas/FADD DD complex and here we report the 2.7 Å crystal structure. The complex shows a tetrameric arrangement of four FADD DDs bound to four Fas DDs. We show that an opening of the Fas DD exposes the FADD binding site and simultaneously generates a Fas/Fas bridge. The result is a regulatory Fas/FADD complex bridge governed by weak protein:protein interactions revealing a model where the complex functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. Thus besides depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signaling solely by oligomerization and clustering events.