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

我们身体中的器官和组织是由数百万个细胞组成的，这些细胞必须非常精确地组织起来，才能产生适当大小和形状的结构。为了实现这一点，细胞之间相互通信，以确保在正确的位置制造正确数量和类型的细胞。因此，这些细胞通讯途径对于确保组织的正确构建和在整个生命过程中得到适当的维护非常重要。它们的交流依赖于所谓的受体，即存在于细胞表面的蛋白质，与另一个细胞产生的信号蛋白--配体--正确地相互作用。Noch就是这样一种重要的受体，它的正常活动对组织的发育和维持至关重要，其不适当的活动与包括癌症在内的许多疾病有关。因此，了解它的配体是如何运作的非常重要，因为这可能会对疾病治疗产生影响。我们的研究调查了一个新的假说，该假说是从对Notch配体所采用的形状的研究中出现的。它们的形状表明，这些信号蛋白可能会接触细胞表面，即细胞膜，以帮助它们找到或粘着Notch受体。因为我们可以设计配体形状的细微变化，我们可以直接检验这一假设，并区分膜结合对其有效信号传递能力的具体贡献。我们将通过设计果蝇基因组的变化来实现这一点，并观察这如何影响果蝇组织的组织方式。对于这些研究来说，苍蝇是一个强大的系统，因为它包含了所有关键的参与者，事实上，超过75%的人类致病基因存在于苍蝇身上，但它很容易和快速地被操纵。我们的结果将有可能改变目前对配体如何与Notch受体承载细胞相互作用的理解。因此，他们将产生广泛的影响，并可能提出新的策略来帮助治疗与Notch相关的疾病。

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.