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Updated: Jul 15, 2026
05:48
Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
Published on: January 2, 2018
Structural basis for autoinhibition of Notch
Wendy R Gordon1, Didem Vardar-Ulu, Gavin Histen
1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115, USA.
Nature Structural & Molecular Biology
|April 3, 2007
Summary
The Notch receptor
Area of Science:
- Cellular biology
- Structural biology
- Biochemistry
Background:
- Notch receptors mediate crucial cell-to-cell communication.
- Ligand binding triggers metalloprotease cleavage within the Notch negative regulatory region (NRR).
- This cleavage is essential for initiating Notch signaling.
Purpose of the Study:
- To elucidate the structural basis of Notch receptor autoinhibition.
- To understand the mechanism of metalloprotease site exposure during Notch activation.
- To investigate the role of specific mutations in Notch signaling deregulation.
Main Methods:
- X-ray crystallography of the human NOTCH2 NRR.
- Analysis of interdomain interactions within the NRR.
- Structural comparison with mutated NOTCH1 NRR (inferred).
Main Results:
- The human NOTCH2 NRR adopts an autoinhibited conformation in its crystal structure.
- Extensive interdomain interactions shield the metalloprotease cleavage site.
- Significant conformational changes are required to expose the cleavage site upon ligand binding.
Conclusions:
- The autoinhibited structure explains how Notch signaling is kept in check.
- Ligand binding likely induces a conformational shift to permit protease access.
- Leukemia-associated mutations may disrupt the NRR's hydrophobic core, releasing autoinhibition.
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The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
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The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
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