Fig. (1) The 6 human DD-containing receptors and their known ligands.The six human DD-containing receptors, TNF-R1 (p55/p60 TNF-R), CD95 (Fas, APO-1), death receptor 3 (DR3, TRAMP), TRAIL-R1 (DR4), TRAIL-R2 (DR5) and DR6 (TNFRSF21) are activated by their respective ligands: TNF, CD95L (FasL/APO-1L), TL1A, TRAIL (Apo2L), and a specific amino-terminal cleavage fragment of the β-amyloid precursor protein (APP), N-APP. They are transmembrane proteins which contain repeats of 2-4 cysteine-rich domains (CRDs) in the extracellular portion required for ligand binding and an intracellular death domain (ICD) capable of recruiting specific adaptors proteins. Whilst the primary signal output of the TRADD-recruiting ICDs of TNF-R1 and DR3 (shown in dark grey) is the activation of inflammatory signalling, the FADD-recruiting ICDs of CD95 and the TRAIL death receptors (shown in light grey) induce apoptosis as their primary signalling output.