Death receptors are members of the tumour
necrosis factor (
TNF) receptor superfamily characterised by an ~80
amino acid long alpha-helical fold, termed the death domain (DD).
Death receptors diversified during early vertebrate evolution indicating that the DD fold has plasticity and specificity that can be easily adjusted to attain additional functions. Eight members of the
death receptor family have been identified in humans, which can be divided into four structurally homologous groups or clades, namely: the p75(NTR) clade (consisting of
ectodysplasin A receptor,
death receptor 6 (DR6) and p75
neurotrophin (NTR) receptor); the tumour
necrosis factor receptor 1 clade (
TNFR1 and DR3), the CD95 clade (CD95/FAS) and the
TNF-related apoptosis-inducing ligand receptor (TRAILR) clade (TRAILR1 and TRAILR2). Receptors in the same clade participate in similar processes indicating that structural diversification enabled functional specialisation. On the surface of nearly all human cells multiple
death receptors are expressed, enabling the cell to respond to a plethora of external signals. Activation of different
death receptors converges on the activation of three main signal transduction pathways: nuclear factor-κB-mediated differentiation or
inflammation,
mitogen-associated
protein kinase-mediated stress response and
caspase-mediated apoptosis. While the ability to induce cell death is true for nearly all DRs, the FAS and TRAILR clades have specialised in inducing cell death. Here we summarise recent discoveries about the molecular regulation and structural requirements of apoptosis induction by
death receptors and discuss how this information can be used to better explain the
biological functions, similarities and distinguishing features of
death receptors.