Related Experiment Videos
2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity
1Department of Life Science and School of Environmental Engineering, Pohang University of Science and Technology, Kyungbuk, Korea.
Abstract:
TRAIL is a newly identified cytokine belonging to the large tumor necrosis factor (TNF) family. TRAIL is a novel molecule inducing apoptosis in a wide variety of tumor cells but not in normal cells. To help in elucidating its biological roles and designing mutants with improved therapeutic potential, we have determined the crystal structure of human TRAIL. The structure reveals that a unique frame insertion of 12-16 amino acids adopts a salient loop structure penetrating into the receptor-binding site. The loop drastically alters the common receptor-binding surface of the TNF family most likely for the specific recognition of cognate partners. A structure-based mutagenesis study demonstrates a critical role of the insertion loop in the cytotoxic activity of TRAIL.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death. Its unique structural loop is crucial for this cytotoxic activity and specific receptor binding.
Area of Science:
- Structural biology
- Molecular and cellular biology
- Immunology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine in the TNF family.
- TRAIL selectively induces apoptosis in tumor cells, sparing normal cells.
- Understanding TRAIL's structure is key to its biological roles and therapeutic development.
Purpose of the Study:
- To determine the crystal structure of human TRAIL.
- To elucidate the structural basis for TRAIL's selective apoptosis-inducing activity.
- To guide the design of TRAIL mutants with enhanced therapeutic potential.
Main Methods:
- X-ray crystallography was used to determine the three-dimensional structure of human TRAIL.
- Structure-based mutagenesis was employed to investigate the function of specific structural elements.
- Analysis of the receptor-binding surface and its alterations was performed.
Main Results:
- The crystal structure revealed a unique 12-16 amino acid insertion forming a salient loop.
- This insertion loop significantly modifies the common TNF family receptor-binding surface.
- Mutagenesis studies confirmed the critical role of the insertion loop in TRAIL's cytotoxic function.
Conclusions:
- The unique insertion loop in TRAIL is essential for its specific recognition of receptors.
- This structural feature underlies TRAIL's selective induction of apoptosis in cancer cells.
- The findings provide a structural basis for developing novel TRAIL-based cancer therapeutics.