Every cell in a developing human embryo must decide whether to stick to its neighbours or move to a new location, and a set of receptor molecules on the cell surface makes that call. This project aims to reveal, down to the level of individual atoms, how those receptors work together to control cell adhesion and guidance—for instance, during the wiring of the brain. The problem is that while we know receptors exist, we do not understand the physical choreography by which they integrate signals from outside the cell, across the membrane, and into the cell’s interior. Without that atomic-level picture, we cannot predict how cells will behave when these systems go wrong. If successful, this fundamental science will provide a structural blueprint of receptor signalling mechanisms. That blueprint could eventually be exploited to design molecules that repair nerve damage or treat neurological disorders. More broadly, understanding how cells coordinate adhesion and movement is a prerequisite for any future therapy that aims to regrow tissue or guide regenerating nerves—applications that remain distant but are now grounded in concrete molecular detail.
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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.
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