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Notch ligand delta-like1: X-ray crystal structure and binding affinity.
Nadia J Kershaw1, Nicole L Church1, Michael D W Griffin2
1*Department of Structural Biology, Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, 3052 Australia.
The Biochemical Journal
|February 27, 2015
Summary
We determined the X-ray crystal structure of the Notch ligand delta-like ligand-1 (Dll-1), revealing its extended conformation. This structural insight clarifies similarities and differences between Notch ligands, aiding understanding of receptor interactions.
Area of Science:
- Structural Biology
- Molecular Biology
- Biochemistry
Background:
- The Notch pathway is crucial for cell signaling in multicellular organisms.
- Understanding Notch ligand structure is key to deciphering cell-cell communication.
Purpose of the Study:
- To determine the X-ray crystal structure of the extracellular domain of delta-like ligand-1 (Dll-1).
- To compare Dll-1 structure with Jagged1 to identify similarities and differences in ligand families.
- To investigate the binding affinity of Dll-1 with Notch1.
Main Methods:
- X-ray crystallography to determine protein structure.
- Analytical ultracentrifugation to confirm conformation and measure binding affinity.
- Biochemical assays to explore ligand-receptor interactions.
Main Results:
- The extracellular domain of Dll-1 adopts a highly extended conformation.
- Structural comparison reveals differences in C2 domains between Dll-1 and Jagged1, suggesting varied lipid-binding properties.
- A conserved hydrophobic patch on both ligands likely serves as a common receptor-interaction site.
- Binding affinity (Kd) of Dll-1 for Notch1 was determined to be 10 μM using solution-based analytical ultracentrifugation.
Conclusions:
- The determined structure provides a molecular basis for understanding Notch ligand function.
- Structural variations between Dll-1 and Jagged1 highlight distinct mechanisms within the Notch signaling pathway.
- Accurate binding affinity measurements clarify previous discrepancies in the literature regarding Dll-1/Notch1 interaction.
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