The binding of TNF-α to TNFR1 results in captor trimerisation and clustering of intra cellular death domains.
The Death Domains (DDs), the Death Effector Domains (DEDs), the CAspase Recruitment Domains (CARDs) and the PYrin Domains (PYDs) constitute key building blocks involved in the assembly of multimeric complexes implicated in signaling cascades leading to inflammation and cell death.
Several TRAIL receptors have been identified: two of these receptors TRAIL-R1/DR4 and TRAIL-R2/DR5 contain cytoplasmic death domains and signal apoptosis, while two other decoy receptors, TRAIL-R3/DcR1 and TRAIL-R4/DcR2 lack a functional death domain and do not mediate apoptosis.
Binding of FasL to Fas results in trimerization of Fas, which includes the approximation of death domains in the cytoplasmic tails of Fas.
In this respect, however, it should be mentioned that TRAIL-R1 and TRAIL-R2, which contain cytoplasmic "death domains", not only mediate pro-apoptotic signals but can also promote cell type-dependent pro-survival and proliferation signals [8] [12].
Pyrin contains the PYD domain, which belongs to a member of the six-helix bundle, death-domain superfamily that includes death domains, death effector domains, and caspase activation and recruitment domains (CARDs).
Stimulation of Fas/CD95 results in receptor aggregation and recruitment of the adapter molecule Fas-associated death domain-containing protein (FADD), through interaction between its own death domain and the clustered receptor death domains.
Similar interactions have been detected between MyD88 and other proteins lacking TIR and death domains such as Bruton's tyrosine kinase [23], phosphatidyl-inositol-3-OH kinase [24], and interferon regulatory factor 7 (IRF7) [25].
Stimulation of Fas results in the oligomerization of its receptors and the recruitment of the adaptor molecule FADD through the interaction of death domains from both parts, which results in the recruitment of procaspase-8 and the formation of DISC.
Although it has been suggested that death receptor-mediated apoptosis may not be functional in non-chordate invertebrates [19], the presence of both initiator domains in mussel, as along with previously reported descriptions of several proteins containing death domains from other invertebrates [14], [39], suggest that there is the possibility of a death receptor-mediated pathway in invertebrates.
Interactions between Fas and FADD via their C-terminal death domains expose the N-terminal death effector domain (DED) of FADD, which can interact with DED domains in the caspase-8 proform, resulting in the oligomerization of this protease and its subsequent autocleavage and activation [45] [48].
