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Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor

A Truneh1, S Sharma, C Silverman

  • 1Department of Immunology, SmithKline Beecham Pharmaceuticals, Pennsylvania, King of Prussia, PA 19406, USA. alem_truneh@sbphrd.com

The Journal of Biological Chemistry
|April 20, 2000
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor binding affinity is temperature-dependent. At physiological temperatures, TRAIL preferentially binds to DR5, influencing apoptosis and disease roles.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces apoptosis via DR4 and DR5 receptors.
  • TRAIL also interacts with decoy receptors (DcR1, DcR2) and OPG, but their role in resistance is unclear.
  • Previous studies suggested TRAIL binds all receptors with similar high affinities.

Purpose of the Study:

  • To investigate the temperature-dependent binding affinities of TRAIL to its receptors.
  • To determine if TRAIL exhibits preferential binding to specific receptors at physiological temperatures.

Main Methods:

  • Isothermal titration calorimetry (ITC) was used to measure binding affinities.
  • Competitive enzyme-linked immunosorbent assays (ELISA) were performed.
  • Cell surface binding assays were conducted.

Main Results:

  • TRAIL receptor affinities are highly temperature-dependent.
  • At 4°C, TRAIL shows similar affinities for DR4, DR5, DcR1, and OPG.
  • At 37°C (physiological temperature), TRAIL exhibits significantly different affinities, with highest affinity for DR5 (K(D) ≤ 2 nm) and lowest for OPG (K(D) = 400 nm).
  • Preferential binding of TRAIL to DR5 was also observed on cell surfaces.

Conclusions:

  • The rank order of TRAIL receptor affinities changes substantially with temperature.
  • Significant, previously unobserved affinity differences for TRAIL receptors exist at physiological temperatures.
  • These findings are crucial for understanding the complex roles of TRAIL in physiological and pathological contexts.

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