Apoptosis is deregulated in many cancers, making it difficult to kill tumours. Drugs that restore the normal apoptotic pathways have the potential for effectively treating cancers that depend on aberrations of the apoptotic pathway to stay alive. Apoptosis targets that are currently being explored for cancer drug discovery include the tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors, the BCL2 family of anti-apoptotic proteins, inhibitor of apoptosis (IAP) proteins and MDM2.

Promoting apoptosis as a strategy for cancer drug discovery

https://www.cell.com/immunity/pdf/S1074-7613(00)80212-5.pdf

Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5.

The molecular architecture of the TNF superfamily

Tumour Necrosis Factor alpha (TNF alpha), is an inflammatory cytokine produced by macrophages/monocytes during acute inflammation and is responsible for a diverse range of signalling events within cells, leading to necrosis or apoptosis The protein is also important for resistance to infection and cancers TNF alpha exerts many of its effects by binding, as a trimer, to either a 55 kDa cell membrane receptor termed TNFR-1 or a 75 kDa cell membrane receptor termed TNFR-2 Both these receptors belong to the so-called TNF receptor superfamily The superfamily includes FAS, CD40, CD27, and RANK The defining trait of these receptors is an extra cellular domain comprised of two to six repeats of cysteine rich motifs Additionally, a number of structurally related "decoy receptors" exist that act to sequester TNF molecules, thereby rescuing cells from apoptosis The crystal structures of TNF alpha, TNF beta, the extracellular domain of TNFR-1 (denoted sTNFR-1), and the TNF beta sTNFR-1 complex have been defined by crystallography This article will review the structure/function relationships of the TNF alpha and the TNF receptor superfamily It will also discuss insights as to how structural features play a role in the pleiotropic effects of TNF alpha

TNF alpha and the TNF receptor superfamily: structure-function relationship(s).

Apo2 ligand or tumour necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is one of the several members of the tumour necrosis factor (TNF) gene superfamily that induce apoptosis through engagement of death receptors (DRs). Apo2L/TRAIL interacts with an unusually complex receptor system of two DRs and three decoys. This protein has garnered intense interest as a potential candidate for cancer therapy because as a trimer it selectively induces apoptosis in many transformed cells but not in normal cells. While much of the early characterisation of Apo2L/TRAIL and its receptors relied on overexpression studies, recent work using untransfected cells has clarified how endogenous proteins transmit apoptotic signals from this ligand. In this review, we focus on the apoptotic signalling pathways stimulated by Apo2L/TRAIL and summarise what is known about its physiological role.

/pdf/apo2l-trail-and-its-death-and-decoy-receptors-4852k7o927.pdf

Apo2L/TRAIL and its death and decoy receptors.

TRAIL, an apoptosis inducing ligand, has at least four cell surface receptors including the death receptor DR5. Here we report the crystal structure at 2.2 A resolution of a complex between TRAIL and the extracellular region of DR5. TRAIL forms a central homotrimer around which three DR5 molecules bind. Radical differences in the surface charge of the ligand, together with variation in the alignment of the two receptor domains confer specificity between members of these ligand and receptor families. The existence of a switch mechanism allowing variation in receptor domain alignment may mean that it is possible to engineer receptors with multiple specificities by exploiting contact positions unique to individual receptor-ligand pairs.

N Chen

Papers

Structure of the TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation