Related Experiment Videos
Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5
S G Hymowitz1, H W Christinger, G Fuh
1Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA.
Abstract:
Formation of a complex between Apo2L (also called TRAIL) and its signaling receptors, DR4 and DR5, triggers apoptosis by inducing the oligomerization of intracellular death domains. We report the crystal structure of the complex between Apo2L and the ectodomain of DR5. The structure shows three elongated receptors snuggled into long crevices between pairs of monomers of the homotrimeric ligand. The interface is divided into two distinct patches, one near the bottom of the complex close to the receptor cell surface and one near the top. Both patches contain residues that are critical for high-affinity binding. A comparison to the structure of the lymphotoxin-receptor complex suggests general principles of binding and specificity for ligand recognition in the TNF receptor superfamily.
Insights
The crystal structure reveals how Apo2L (TRAIL) binds DR5, triggering apoptosis. This finding provides insights into TNF receptor superfamily ligand recognition and specificity.
Area of Science:
- Structural Biology
- Molecular Biology
- Immunology
Background:
- Apoptosis is initiated by the formation of a complex between Apo2L (TRAIL) and its signaling receptors DR4 and DR5.
- This complex formation triggers apoptosis by inducing the oligomerization of intracellular death domains.
Purpose of the Study:
- To determine the crystal structure of the complex between Apo2L and the ectodomain of its signaling receptor DR5.
- To elucidate the molecular interactions governing the binding of Apo2L to DR5.
Main Methods:
- X-ray crystallography was employed to determine the structure of the Apo2L-DR5 ectodomain complex.
- Structural analysis was performed to identify key binding interfaces and residues.
Main Results:
- The crystal structure revealed three elongated DR5 receptors bound to the homotrimeric Apo2L ligand.
- The interface between Apo2L and DR5 is characterized by two distinct patches critical for high-affinity binding.
- Comparison with the lymphotoxin-receptor complex structure suggests general principles of ligand recognition in the TNF receptor superfamily.
Conclusions:
- The determined structure provides a detailed molecular understanding of Apo2L-DR5 complex formation.
- This structural information is crucial for understanding the mechanism of TRAIL-induced apoptosis.
- The findings offer insights into ligand binding and specificity within the TNF receptor superfamily.