Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)
The extrinsic apoptosis pathway is triggered by extra-cellular ligands of the TNF superfamily (TNFSF) that bind to their respective death receptors in the plasma membrane of the cell (1–2). There are five -studied ligand (L)–death-receptor (DR) complexes (Figure 30.1). TNF (tumor necrosis factor) binds to its receptors TNF-R1, expressed on most cell types or to TNFR2. Only TNF-R1 contains a death domain (DD) to directly signal apoptosis, but signaling through TNF-R2 to degrade several E3 ubiquitin ligases also leads to cell death. FasL (CD95L) typically induces death of immune cells by binding to the receptor Fas (CD95/Apo1/DR2). TWEAK (Apo3L) binds to the receptor TRAMP (DR3/Apo3/Wsl1), and TRAIL (Apo2L) binds to two different receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) (3–4) to trigger apoptosis.
Death ligands are initially produced as type II transmembrane proteins (intra-cellular N-terminus and extra-cellular C-terminus). Their conserved C-terminal TNF homology domain (THD), which is crucial for receptor binding, is prone to assemble into biologically active homotrimers. These ligands can remain membrane bound or they can be released into the extracellular space as soluble trimers through limited proteolysis. The potency of soluble ligands to induce death can be decreased or abolished compared to membrane-associated forms (5–7).
Death receptors belong to the TNF receptor superfamily (TNFRSF) (2,8; Figure 30.1). They are type I transmembrane proteins (extra-cellular N-terminus and intra-cellular C-terminus), characterized by multiple extra-cellular cysteinerich domains (CRDs) and an intra-cellular death domain (DD). The CRDs are responsible for ligand binding and are usually arranged in an elongated rod-like structure stabilized by a ladder of disulfide bonds (9–10). Three-dimensional structure determinations indicate that one trimeric ligand interfaces with three TNF receptors (9,11–12). Originally it was thought that trimerization of the death receptors is induced upon ligand binding. Later evidence indicates that in the absence of ligands, death receptors exist as pre-assembled homotrimers through their N-terminal pre-ligand assembly domain (PLAD; 13–14), and that ligand–receptor binding leads to further conformational changes to activate signaling.
Figure 30.1. Interaction of death ligands with their corresponding death receptors. Trimeric cell death-inducing protein ligands bind to specific plasma-membrane-embedded death receptors (DR) containing extra-cellular cysteine-rich domains and intra-cellular death domains (DD).