Figure 1.

Signaling triggering: proposed mechanisms. (A) Triggering by intracellular domain (ID) juxtaposition imposed by tumor necrosis factor (TNF) family ligands, and its restriction by the pre-ligand assembly domain (PLAD). (B) Triggering potentiation by anchorage of ligands to membranes. (C) Triggering by ID distancing: A fraction of the nerve growth factor receptor (NGFR) molecules occurs as dimers of receptor molecules that are covalently linked through a conserved transmembrane (TM) cysteine residue. In these dimers, the intracellular death domains (DDs) seem to be constitutively associated. Neurotrophin-induced triggering of these dimers to signal for death was suggested to occur by distancing of the IDs, imposed rather like a snail tongue, with the TM cysteine link serving as a fulcrum (Vilar et al. 2009). (See discussion of these findings in the last paragraph of this review.)