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The tumor necrosis factor receptor (TNF R) superfamily is a large family of cell surface receptors involved in lymphocyte development and function. These proteins share significant homologies within their extracellular ligand binding domains and intracellular effector domains. 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. CRD2 and CRD3 form the ligand binding pocket for TNF-α.

The amino terminal regions of the extracellular domains of both TNF RI and TNF RII can self-associate (trimerication) in the absence of TNF-α ligand. This domain has been termed the PLAD, pre-ligand-binding assembly domain. Although physically distinct from the ligand contact domain (i.e. CDR2/3), the PLAD is essential for TNF-α binding and receptor function. Either a death or a survival signal is initiated upon activation of caspase signalling pathways or the NF-κ B pathway, respectively. Deletion of the PLAD completely abolishes ligand binding, thus suggesting that TNF-α /TNF R binding is dependent upon receptor self-assembly. Additional members of the TNF R superfamily , including TRAIL RI, CD40 and Fas, also self-associate, thus indicating that the PLAD may be a conserved feature among TNF R superfamily members.