Structure/Function Implications of Phospholipid Recognition by Notch-Ligands

Notch信号通路是细胞生物学中调节许多不同决定的重要信号转导子。这些对于胚胎发育和成年组织的维持至关重要。在其最简单的形式中，细胞外蛋白/配体通过与细胞外部的Notch受体蛋白结合来激活途径。这导致裂解事件，使得受体的细胞内部分被释放，行进到细胞核，在那里它形成复合物以激活负责调节细胞行为的特定基因。Notch活性的异常丧失或获得与许多人类发育障碍、成人发病疾病和癌症相关，使其成为治疗干预的关键靶标。我们最近已经确定了一个新的性质的活化剂或配体的Notch信号，这表明配体可以结合到磷脂。磷脂是形成限制性细胞膜和具有各种运输功能的囊泡的主要组分的分子。该项目旨在详细了解配体如何与磷脂结合，以及这种相互作用如何影响Notch结合，信号传导和调节。这将使我们对Notch信号通路的工作原理、与该通路相关的各种疾病的发生机制有新的认识，并将为我们设计药物（如单克隆抗体或小分子激活剂或抑制剂）提供新的方法，这些方法在临床和/或研究环境中操纵Notch信号可能是非常宝贵的。

The Notch signalling pathway is an essential signal transducer which regulates many different decisions in cell biology. These are crucial for embryonic development and for the maintenance of adult tissue. In its simplest form an extracellular protein/ ligand activates the pathway by binding to the Notch receptor protein on the outside of the cell. This leads to a cleavage event such that the intracellular portion of the receptor is released, travels to the nucleus, where it forms a complex to activate specific genes responsible for regulating cell behaviour. Aberrant loss or gain of Notch activity is associated with many human developmental disorders, adult onset diseases and cancers, making it a key target for therapeutic intervention. We have recently identified a new property of one of the activators or ligands of Notch signalling, which indicates the ligand can bind to phospholipids. Phospholipids are molecules which form the major component of the limiting cell membrane and vesicles with various transport functions. This project aims to understand in great detail how the ligand binds to phospholipid and how this interaction affects Notch binding, signalling and regulation. This will give us new insights into how the Notch signalling pathway works, how various diseases linked to the pathway arise, and will give us new ways of designing drugs such as monoclonal antibodies or small molecule activators or inhibitors .These may prove invaluable in a clinical and/ or research setting to manipulate the Notch signal.