Figure 7: A novel two-step DISC model.

(a) Proposed model of DISC assembly: following binding of TRAIL to DR5, the DD of the death receptor become available for interaction with DD of FADD. Once bound via its DD to a DR, the DED of FADD (green chevrons) can form protein–protein interactions with the DEDs of procaspase 8 (purple chevrons) and FLIP (orange chevrons) (step 1). Owing to their relative binding affinities, FLIP is primarily recruited to the α1/α4 face of FADD and procaspase 8 to the α2/α5 surface to form intermediate tripartite complexes. Individual tripartite complexes then interact with one another via interactions between the α1/α4 face of FLIP and the α2/α5 surface of procaspase 8 (step 2). When FLIP(S) is recruited to the α1/α4 surface of the FADD DED, procaspase 8 remains unprocessed; however, when FLIP(L) is recruited, interaction with procaspase 8 in an adjacent DED trimer would allow interaction between the caspase-like domain of FLIP(L) and the caspase domain of caspase 8, leading to formation of the apoptosis-incompetent, membrane-restricted but catalytically active p43-FLIP(L)-p41/43-caspase 8 enzyme that can act on local substrates such as RIPK1. When FLIP levels become depleted (for example, at high levels of receptor stimulation), procaspase 8 is recruited more frequently to the α1/α4 surface of the FADD DED as well as the α2/α5 surface, interactions between adjacent trimers can now lead to the formation of procaspase 8 homodimers and processing into the apoptosis-competent caspase. (b) Molecular modelling of the proposed FADD-procaspase 8-FLIP/procaspase 8-FADD interactions at the DISC.