Structure/Function Implications of Phospholipid Recognition by Notch-Ligands

Notch信号通路是调节细胞生物学中许多不同决策的重要信号转导途径。这些对于胚胎发育和成人组织的维持都是至关重要的。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该途径。这导致了一个切割事件，使受体的细胞内部分被释放，进入细胞核，在那里形成一个复合体，激活负责调节细胞行为的特定基因。Notch活性的异常丧失或增强与许多人类发育障碍、成人发病疾病和癌症有关，使其成为治疗干预的关键靶点。我们最近发现了一种新的Notch信号激活剂或配体的性质，这表明该配体可以与磷脂结合。磷脂是构成限制细胞膜和囊泡的主要成分的分子，具有各种转运功能。该项目旨在更详细地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、信号传递和调节。这将使我们对Notch信号通路如何工作，以及与该通路相关的各种疾病是如何发生的有了新的见解，并将为我们设计诸如单抗或小分子激活剂或抑制剂等药物提供新的方法。这些可能在临床和/或研究环境中被证明是非常有价值的来操纵Notch信号。

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.