Figure 5
From: DED or alive: assembly and regulation of the death effector domain complexes
Processing of procaspase-8. When two procaspase-8 molecules are co-recruited to the DISC via their DEDs, their caspase domains undergo conformational changes that exposes the enzymatic activity necessary for cleavage of the C-terminal portion of the caspase, liberating a p12 subunit, which is subsequently processed to the small p10 catalytic subunit. This initial processing step may occur in an inter-dimer manner between adjacent procaspase-8 dimers rather than the intra-dimer manner depicted.63 The 41/43 kDa caspase-8 intermediates cleave one another in a trans-catalytic manner in the region between their DEDs and the large p18 catalytic subunit. The two molecules of pro-caspase-8 that are subsequently released associate with the two p10 subunits to form the active protease.57 At lower levels of DISC stimulation or when FLIP is highly expressed, FLIP/caspase-8 heterodimers assemble at the DISC via interactions between their DEDs and those of FADD.48 The pseudo-caspase domain of FLIPL is able to induce the conformational change in procaspase-8’s caspase domain that is necessary to create its active site.59 The FLIPL:caspase-8 heterodimer is processed between the p18 and p12 subunits of both proteins, but is unable to be further processed owing to FLIPL’s lack of enzymatic activity, and this heterodimer is unable to activate apoptosis. In the case of FLIPS, heterodimerisation fails to activate procaspase-8 as the initial conformational change cannot take place in procaspase-8’s caspase domain
