Fig. 7. Proposed bidirectional DED assembly mechanisms in forming the ternary complex of cFLIP, FADD, and procaspase-8 in determining cell fate.

a Proposed DED assembly mechanism in the reverse hierarchical binding process. When cFLIP levels are elevated, some cFLIP molecules could initiate the formation of a transient cFLIP double-layer intermediate complex. This intermediate complex recruits endogenous Casp-8 and cFLIP to form a stable binary complex. The resultant cFLIP-Casp-8 binary complex subsequently utilizes the CBS to recruit endogenous FADD and loses excess cFLIP molecule, resulting in a ternary cFLIP-Casp-8-FADD complex. This complex, similar to the one formed through the hierarchical binding process, provides resistance to apoptosis and necroptosis. Together with the hierarchical binding process shown in (b), the reverse hierarchical binding process completes the bidirectional DED assembly mechanism. b Proposed DED assembly mechanism in the hierarchical binding process⁵⁶. Upon high levels of FADD or a high local concentration of FADD, FADD initiates the formation of a transient binary intermediate complex with endogenous Casp-8. cFLIP targets the CBS of this intermediate complex to block apoptotic signaling, resulting in a ternary FADD-Casp-8-cFLIP complex. When cFLIP is depleted, the intermediate complex could recruit endogenous procaspase-8 to initiate apoptosis. Blue and green ribbons represent cFLIP and Casp-8, respectively. FADD molecules are colored as their counterparts in Fig. 1d.