The structural basis of cell surface receptor signalling mechanisms.

一个多细胞生物体的细胞，比如人类，在发育过程中必须经历一个精致的舞蹈。每一个细胞都必须在发育中的有机体中的特定时间和地点实现与其作用相适应的粘附性和运动性之间的特定平衡。指导每个细胞的大部分信息必须通过与包括相邻细胞在内的直接环境的相互作用来获得。这些相互作用由嵌入细胞表面的各种类型的受体分子介导。我们希望了解受体如何协同工作，以控制细胞粘附或向特定方向移动的能力。利用结构生物学的技术，我们的目标是显示在原子细节受体控制细胞粘附和指导的机制，例如在一个系统，指导大脑的布线。这些机制必须整合细胞之间和同一细胞表面上发生的受体相互作用，以及从细胞外环境到细胞内环境的跨越。为了深入了解这样的系统，我们将需要使用我们以前的MRC资助的研究中开发的最先进的技术，以产生合适的样品的跨膜受体和复合物，并结合联合收割机在体外结构的分离分子的研究与原位分析在功能相关的背景下的细胞表面。最终，利用我们揭示的机制来修复神经损伤或治疗各种神经系统疾病可能被证明是可能的。

The cells of a multicellular organism, such as a human, must be subject to an exquisite choreography during development. Each cell must achieve the particular balance between adhesion and motility appropriate to its role at a specific time and place in the developing organism. Much of the information to direct each cell must be garnered through interaction with its immediate environment including neighbouring cells. These interactions are mediated by various types of receptor molecules embedded in the cell surface. We wish to understand how sets of receptors work together to control the ability of a cell to stick (adhere) or to move in a specific direction. Using the techniques of structural biology we aim to show in atomic detail the mechanisms by which receptors control cell adhesion and guidance, for example in a system which directs the wiring of the brain. These mechanisms must integrate receptor interactions occurring between cells and on the same cell surface, as well as spanning from the extracellular to the intracellular environment. To generate insight into such systems we will need to use state of the art techniques developed during our previous MRC funded studies to produce suitable samples of membrane spanning receptors and complexes and to combine in vitro structural studies on the isolated molecules with in situ analyses in the functionally relevant context of the cell surface. Ultimately it may prove possible to exploit the mechanisms we reveal to repair nerve damage or to treat various neurological disorders.