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. 2013 Nov;140(2):186-99.
doi: 10.1016/j.pharmthera.2013.06.009. Epub 2013 Jul 8.

Structural Determinants of DISC Function: New Insights Into Death Receptor-Mediated Apoptosis Signalling


Structural Determinants of DISC Function: New Insights Into Death Receptor-Mediated Apoptosis Signalling

Tamas Sessler et al. Pharmacol Ther. .


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.

Keywords: ALPS; ASM; Acidic sphingomyelinase; Apoptosis; Autoimmune lymphoproliferative syndrome; CRD; Cellular FLICE inhibitory protein; Cellular inhibitor of apoptosis protein; Crystal structure; Cysteine rich domain; DD; DED; DISC; DR; Death domain; Death effector domain; Death receptor; Death-inducing signalling complex; EDA (EDA-A1); EDAR; EDAR-associated death domain; EDARADD; Ectodysplasin A; Ectodysplasin A receptor; FADD; FAS Associated Death Domain containing protein; Fas receptor ligand; FasL; IKK; IRAK; Inhibitor of kappa B kinase; Inhibitor of kappa-B protein; Interleukin-1 receptor-associated kinase; IκB; JNK; MAPK; Mitogen activated protein kinase; NF-κB; Nuclear factor-kB; PARP; PI3K; PIDD; PLAD; PYD; Phosphatidylinositol 3-kinase; Poly ADP ribose polymerase; Posttranslational modification; Pre-Ligand Assembly Domain; Pyrin Domains; RIP1 (RIPK1); Receptor interacting protein kinase 1; SM; Sphingomyelinase; TAB2; TAK1-binding protein 2; TL1A; TNF; TNF Receptor Associated Death Domain protein; TNF receptor-associated factor; TNF-like ligand 1A; TNFR1 (p55); TRADD; TRAF; TRAIL (Apo2L); Tumour necrosis factor; Tumour necrosis factor receptor 1; Tumour necrosis factor-related apoptosis-inducing ligand; c-Jun N-terminal kinase; cFLIP; cIAP; p53-Induced Death Domain; p75 neurotrophin receptor; p75(NTR).

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