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Structure of the TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation

J Mongkolsapaya1, J M Grimes, N Chen

  • 1MRC Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.

Nature Structural Biology
|December 14, 1999
PubMed

Insights

The crystal structure reveals how Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) binds to its receptor DR5, detailing the molecular interactions that control cell death signaling pathways.

Area of Science:

  • Structural Biology
  • Molecular Biology
  • Immunology

Background:

  • Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a key mediator of apoptosis.
  • TRAIL interacts with multiple cell surface receptors, including Death Receptor 5 (DR5), to initiate programmed cell death.

Purpose of the Study:

  • To elucidate the structural basis of the interaction between TRAIL and the extracellular domain of DR5.
  • To understand the molecular mechanisms conferring specificity in TRAIL-receptor interactions.

Main Methods:

  • X-ray crystallography was employed to determine the structure of the TRAIL-DR5 complex at 2.2 Å resolution.

Main Results:

  • The crystal structure reveals that TRAIL forms a homotrimer, with three DR5 molecules binding around it.
  • Significant differences in surface charge between TRAIL and DR5, along with variable receptor domain alignment, dictate binding specificity.
  • A potential switch mechanism in receptor domain alignment was identified.

Conclusions:

  • The determined structure provides critical insights into the molecular recognition events governing TRAIL-mediated apoptosis.
  • Understanding these interactions may enable the engineering of novel receptors with altered or multiple specificities for therapeutic applications.

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