Structures of TNF Receptors and Their Interactions With Ligands

The tumor necrosis factor receptors (TNFRs), in conjunction with their ligands, influence many important biological processes, including activation of apoptosis, modulation of the immune system, and regulation of developmental pathways in some tissue types. Some TNFRs positively regulate cell growth, whereas others initiate apoptotic pathways upon stimulation by ligand (1). These contradictory biological activities are determined to some extent by differences in the intracellular domains of these receptors. In particular, a subfamily of TNFRs, termed the death receptors, including TNFR1, Fas, death receptor (DR)3, DR4, DR5, DR6, EDAR, and p75NGFR, all contain an intracellular death domain, and many but not all of these receptors activate apoptotic pathways. None of the other members of the TNFR family identified to date contain recognizable intracellular domains, and instead present binding sites for interactions with TNF receptor-associated factors (TRAFs) and other adaptor proteins.