Functional roles of the C2 phospholipid-binding domain in Notch ligands

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The organs and tissues in our bodies are built from millions of cells that have to be organized with great precision to generate the appropriately sized and shaped structures. To achieve this, the cells communicate with one another to ensure that the right number and type of cells are made in the correct places. These cell communication pathways are therefore very important in ensuring that tissues are built correctly and are properly maintained throughout life. Their communication relies on so-called receptors, proteins that are present at the surface of the cell, interacting correctly with a signalling protein --a ligand-- produced by another cell. Notch is one such essential receptor, whose normal activity is critical for tissue development and maintenance and whose inappropriate activity is associated with many diseases including cancers. Understanding how its ligands operate is therefore very important, as this could have implications for disease treatments. Our research investigates a novel hypothesis that has emerged from studies of the shape adopted by the Notch ligands. Their shapes suggest that these signalling proteins may contact the cell surface, the membrane, to help them find or stick to the Notch receptor. Because we can engineer subtle changes in the ligand shapes, we can directly test this hypothesis and distinguish the specific contribution that membrane binding makes to their ability to signal effectively. We will do this by engineering the changes in the genome of the fruit fly and looking at how this impacts on the way its' tissues are organized as a consequence. The fly is a powerful system for these studies as it contains all of the key players, indeed over 75% of human disease-causing genes are present in flies, yet it is easily and rapidly manipulated. Our results will have the potential to transform current understanding of how ligands interact with the Notch receptor-bearing cells. They will thus have wide impact and could suggest novel strategies to aid treatment of Notch-related diseases.