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

我们体内的器官和组织是由数以百万计的细胞组成的，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，细胞之间相互沟通，以确保在正确的位置产生正确数量和类型的细胞。因此，这些细胞通信途径对于确保组织的正确构建和生命的适当维护非常重要。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。Notch就是这样一种重要的受体，其正常活动对组织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，了解其配体如何运作非常重要，因为这可能对疾病治疗产生影响。我们的研究调查了一种新的假设，这种假设是从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，帮助它们找到或附着在Notch受体上。因为我们可以设计配体形状的细微变化，我们可以直接测试这个假设，并区分膜结合对它们有效发出信号的能力的具体贡献。我们将通过改造果蝇基因组的变化来做到这一点，并观察这对果蝇组织组织方式的影响。苍蝇是这些研究的一个强大的系统，因为它包含了所有的关键参与者，实际上超过75%的人类致病基因存在于苍蝇中，但它很容易和迅速地被操纵。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，它们将产生广泛的影响，并可能提出有助于治疗缺口相关疾病的新策略。

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.