A Domain in TNF Receptors That Mediates Ligand-Independent Receptor Assembly and Signaling

Abstract

A conserved domain in the extracellular region of the 60- and 80-kilodalton tumor necrosis factor receptors (TNFRs) was identified that mediates specific ligand-independent assembly of receptor trimers. This pre-ligand-binding assembly domain (PLAD) is physically distinct from the domain that forms the major contacts with ligand, but is necessary and sufficient for the assembly of TNFR complexes that bind TNF-alpha and mediate signaling. Other members of the TNFR superfamily, including TRAIL receptor 1 and CD40, show similar homotypic association. Thus, TNFRs and related receptors appear to function as preformed complexes rather than as individual receptor subunits that oligomerize after ligand binding.

The influence of α1-antagonist on the expression pattern of TNF receptor family in primary culture of prostate epithelial cells from BPH patients

“…In the first model the ligand induces trimerization and in the second model the pre-ligand self-assembly was proposed. 32,33 The receptor trimerization (a functional state) should lead to a decreased MFI signal, because of a lower receptor density. We think that doxazosin did not influence the TNFR's oligomerization process and the receptors remained inactive.…”

New insights into apoptosis signaling by Apo2L/TRAIL

“…However, substantial evidence now indicates that certain TNFRs are preassembled into oligomers before ligation (Chan, 2007). Preligand association was first detected for Fas, TNFR1 and TNFR2 (Papoff et al, 1999;Chan et al, 2000;Siegel et al, 2000), which appear to form homotypic trimers in the absence of ligand. A preligand assembly domain (PLAD), located in the first CRD of the receptor, mediates the association between monomers.…”

A novel antiapoptotic mechanism based on interference of Fas signaling by CD44 variant isoforms

“…31 This may concern binding of CD44v to the first contact sites for Fas trimerization, the preligand assembly domain (PLAD). 32 Therefore, these CD44v isoforms could conceivably function as prosurvival molecules by binding to and sequestering the Fas death receptor. We are postulating this mechanism to be responsible for the apoptosis resistance, as seen in many studies on autoimmune diseases or human cancer, in which CD44v expression is prevalent.…”

“…We suggest that the variant region of CD44 may interact with the PLAD (pre-ligand assembly domain) of Fas and may thus prevent transiently its trimerization, which is a prerequisite for FasL binding. 32 Hence, Fas remains inactivated and the death-signaling cascade does not take place …”