Abstract
The Notch receptor is part of a core signalling pathway which is highly conserved in all metazoan species. It is required for various cell fate decisions at multiple stages of development and in the adult organism, with dysregulation of the pathway associated with genetic and acquired diseases including cancer. Although cellular and in vivo studies have provided considerable insight into the downstream consequences of Notch signalling, relatively little is known about the molecular basis of the receptor/ligand interaction and initial stages of activation. Recent advances in structure determination of the extracellular regions of human Notch-1 and one of its ligands Jagged-1 have given new insights into docking events occurring at the cell surface which may facilitate the development of new highly specific therapies. We review the structural data available for receptor and ligands and identify the challenges ahead.
Highlights
Domain architecture of Notch receptorThe extracellular domain (ECD) of the Notch receptor varies from species to species; Drosophila and mammalian receptors are much larger than their counterparts from Caenorabditis elegans, each invariably maintains the same molecular architecture (see review [1])
The Notch receptor is part of a core signalling pathway which is highly conserved in all metazoan species
The extracellular domain (ECD) of the Notch receptor varies from species to species; Drosophila and mammalian receptors are much larger than their counterparts from Caenorabditis elegans, each invariably maintains the same molecular architecture
Summary
The extracellular domain (ECD) of the Notch receptor varies from species to species; Drosophila and mammalian receptors are much larger than their counterparts from Caenorabditis elegans, each invariably maintains the same molecular architecture (see review [1]). In combination with cell aggregation assays, identified EGF domains 11 and 12 of the Drosophila Notch receptor as the major ligand-binding site This region was found to be sufficient to bind in a calcium-dependent manner to Notch ligands, but it did not show full functionality in vivo, indicating that additional sites were involved in Notch activation and regulation [5,6]. The current favoured mechanism is that ligand binding and subsequent initiation of ligand endocytosis generates a mechanical pull on the NRR region which leads to LNR repeats being pulled away unmasking the S2 cleavage site (Fig. 1) This is consistent with experimental data which show a requirement for ligand endocytosis in Notch signalling (see review by Weinmaster in this series). This finding demonstrates how promoter organisation controls responsiveness to Notch signalling
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