Abstract
Recent evidence suggests that TNF-related apoptosis-inducing ligand (TRAIL), a death-inducing cytokine with anti-tumor potential, initiates apoptosis by re-organizing TRAIL receptors into large clusters, although the structure of these clusters and the mechanism by which they assemble are unknown. Here, we demonstrate that TRAIL receptor 2 (DR5) forms receptor dimers in a ligand-dependent manner at endogenous receptor levels, and these receptor dimers exist within high molecular weight networks. Using mutational analysis, FRET, fluorescence microscopy, synthetic biochemistry, and molecular modeling, we find that receptor dimerization relies upon covalent and noncovalent interactions between membrane-proximal residues. Additionally, by using FRET, we show that the oligomeric structure of two functional isoforms of DR5 is indistinguishable. The resulting model of DR5 activation should revise the accepted architecture of the functioning units of DR5 and the structurally homologous TNF receptor superfamily members.
Highlights
Whether ligand-induced clusters of DR5 have a specific structural organization is unknown
We demonstrate that Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) forms receptor dimers in a ligand-dependent manner at endogenous receptor levels, and these receptor dimers exist within high molecular weight networks
The organization of DR5 networks via ligand-induced dimerization may allow for interaction of DR5 TM ␣-helices as receptor TM domains are no longer confined to the 50 Å separation observed in the TRAIL-DR5 complex crystal structure
Summary
Whether ligand-induced clusters of DR5 have a specific structural organization is unknown. Results: Ligand binding results in the formation of death receptor dimers that exist within high molecular weight networks. Conclusion: Ligand-induced DR5 clusters are highly organized networks formed through dimerization of receptor trimers. Recent evidence suggests that TNF-related apoptosis-inducing ligand (TRAIL), a death-inducing cytokine with anti-tumor potential, initiates apoptosis by re-organizing TRAIL receptors into large clusters, the structure of these clusters and the mechanism by which they assemble are unknown. We demonstrate that TRAIL receptor 2 (DR5) forms receptor dimers in a ligand-dependent manner at endogenous receptor levels, and these receptor dimers exist within high molecular weight networks. FRET, fluorescence microscopy, synthetic biochemistry, and molecular modeling, we find that receptor dimerization relies upon covalent and noncovalent interactions between membrane-proximal residues. The resulting model of DR5 activation should revise the accepted architecture of the functioning units of DR5 and the structurally homologous TNF receptor superfamily members
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