Fig. 1: Pre-ligand self-association (PLS) autoinhibits DR5 signaling.

Without TRAIL, the DR5 ECD self-associate to form the “lying down” structures parallel to the surface of the lipid bilayer membrane, which buries some ligand-binding sites and prevents DR5 intracellular DD from recruiting the FAS-associated death effector domain (FADD) protein and procaspase-8 for apoptosis signaling (left). TRAIL ligand binds first to a subset of available sites of the PLS complex causing conformational changes and the exposure of more TRAIL-binding sites. Consequently, DR5 ECDs rise orthogonal to the membrane in an active TRAIL–DR5 signaling complex that clusters via interactions between the transmembrane and intracellular DDs. The active signaling complex results in the formation of DISC, caspase-8 activation and apoptosis or inflammatory signaling (right).