The pre-ligand binding assembly domain: a potential target of inhibition of tumour necrosis factor receptor function

Signalling by the tumour necrosis factor receptors (TNFR) is thought to be mediated by the binding of the trimeric Ligand TNF to three monomeric subun its of the receptor. This Ligand induced trimerisation model of TNFR signal ling is mainly supported by crystallographic data of the p60 TNFR-1 and TNF beta complex in which the trimeric Ligand interdigitates between the indiv idual receptor chains and prevents the receptor subunits from interacting w ith each other. Recently, a domain NH, terminal to the ligand binding domai n in the extracellular region of p60 TNFR-1, p80 TNFR-2 and Fas was identif ied that mediates receptor self association before Ligand binding. This pre -ligand binding assembly domain or PLAD is critical for assembly of functio nal receptor complexes on the cell surface and may provide a potential targ et in the design of future novel therapeutics against diseases mediated by members of the TNFR family of receptors.