The structural basis of cell surface receptor signalling mechanisms.

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.

I propose to dissect the signalling mechanisms of a set of type 1 single membrane spanning receptors. The programme is sub-divided into three project areas each of which addresses aspects of cell adhesion/signalling and the mechanisms by which cell surface receptors can deliver the exquisitely fine local control of information transfer required for embryonic development and tissue morphogenesis.

? Cell guidance: Sema6 ? Plexin A interactions
? Cell adhesion: the FLRTs
? Crosstalk in receptor tyrosine kinase signalling: FLRT ? FGFR, FGFR ? N-cadherin

Detailed structural information for each of these systems is of biomedical relevance and in combination they exemplify an interconnected series of questions pertinent to the mode of action of single membrane spanning receptors in general. What mechanisms control signalling through the cell surface membrane? How is bi-directional signalling orchestrated? What is the role of receptor homo- or hetero- dimerisation verses higher order oligomerisation? How does the interplay of cis interactions, providing crosstalk between receptors on the same cell, and trans interactions, mediating cell-cell communication, function?
To date studies by us and others have provided substantial insight into extracellular receptor architecture and ligand-receptor specificity, the challenge now is to link extracellular recognition with intracellular signalling and to address not just the isolated molecules but rather the interplay of cell surface receptors relevant to function in the cellular context. Based on the methodological developments we made during the previous quinquennium of MRC (and CR-UK) funding it is now timely for us to tackle this next level of complexity.