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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor 5 networks that are highly

Christopher C Valley1, Andrew K Lewis, Deepti J Mudaliar

  • 1Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.

The Journal of Biological Chemistry
|April 13, 2012
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers cell death by forming DR5 receptor clusters. This study reveals DR5 receptor dimers form via membrane-proximal interactions, revising models of TRAIL-mediated apoptosis.

Area of Science:

  • Molecular and Cellular Biology
  • Immunology
  • Biochemistry

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with potential anti-tumor activity.
  • TRAIL initiates apoptosis by inducing the clustering of its receptors, but the precise structure and assembly mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the structural organization and assembly mechanism of TRAIL receptor 2 (DR5) clusters.
  • To investigate the role of receptor-ligand interactions in DR5 dimerization and network formation.

Main Methods:

  • Ligand-dependent receptor dimerization was assessed at endogenous levels.
  • High molecular weight networks were analyzed using FRET, mutational analysis, fluorescence microscopy, synthetic biochemistry, and molecular modeling.
  • Oligomeric structures of DR5 isoforms were compared using FRET.

Main Results:

  • DR5 forms receptor dimers in a ligand-dependent manner.
  • These dimers are part of larger, high molecular weight networks.
  • Receptor dimerization is mediated by covalent and noncovalent interactions involving membrane-proximal residues.
  • Two functional DR5 isoforms exhibit indistinguishable oligomeric structures.

Conclusions:

  • DR5 activation involves the formation of receptor dimers stabilized by membrane-proximal interactions.
  • The findings propose a revised model for DR5 functioning within the TNF receptor superfamily.
  • This work advances the understanding of TRAIL-mediated apoptosis signaling pathways.

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