The tumor necrosis factor receptor (TNF R) superfamily is a large family of cell surface receptors involved in lymphocyte development and function.1-4 These proteins share significant homologies within their extracellular ligand binding domains and intracellular effector domains. For example, the extracellular domains of both TNF RI and TNF RII contain three cysteine-rich domains (CRD1, CRD2 and CRD3) characteristic of TNF R superfamily members and a less conserved, fourth cysteine-rich domain that is membrane-proximal.5 CRD2 and CRD3 form the ligand binding pocket for TNF-alpha.5 Previous studies have shown that TNF R superfamily signaling may be induced upon ligand trimerization of the receptor chains.6-8 Either a death or a survival signal is initiated upon activation of caspase signaling pathways or the NF-kappa B pathway, respectively.9,10
|Fig. 1. The amino terminal regions of the extracellular domains of both TNF RI and TNF RII can self-associate in the absence of TNF-alpha ligand. This domain is referred to as the PLAD, pre-ligand-binding assembly domain.
Chan et al.,11 however, have demonstrated that TNF RI and TNF RII receptor subunits can oligomerize in the absence of ligand (see figure 1). The amino terminal regions of the extracellular domains of both TNF RI and TNF RII can self-associate implicating a separate and distinct functional domain for receptor assembly vs. ligand binding. This domain has been termed the PLAD, pre-ligand-binding assembly domain. Although physically distinct from the ligand contact domain (i.e. CRD2/3), the PLAD is essential for TNF-alpha binding and receptor function. Deletion of the PLAD completely abolishes ligand binding, thus suggesting that TNF-alpha/TNF R binding is dependent upon receptor self-assembly. Additional members of the TNF R superfamily, including TRAIL R1, CD40, and Fas, also self-associate, thus indicating that the PLAD may be a conserved feature among TNF R superfamily members.12,13
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