The structural biology of cell signalling and regulation: multiprotein systems and the achievement of high signal-to-noise ratios. (360G-Wellcome-079281_Z_06_Z)

The control of cell differentiation, growth and proliferation is mediated by the assembly and disassembly of multiprotein complexes. My group has studied the 3-D structures of many such complexes in order to understand the nature ofthe interactions, organisation and cooperativity; examples are FGFR, human recombinase Rad51, the breast cancer associated gene product BRCA2, and Cdk6 with cell cycle inhibitor p19INK4d. We have shown that pair-wise interactions are often weak and ill-defined but lead to cooperative assembly of multiprotein complexes with well defined structures, so providing better signal-to-noise ratios in signalling. In this proposal I focus on other features that are shared between multiprotein systems at the cell surface, in the cytoplasm and in the nucleus. I plan to investigate 3-D structural features of complexes where: 1. One or more components are disordered prior tobinding. 2. Higher order clustering modulates signal transduction.3. Glycosylation controls receptor interactions. 4. Different assemblies regulatedifferent signalling pathways. In order to achieve these objectives I plan notonly to extend studies on systems where we have worked before, for example FGFR, Met receptor and Xrcc4; but also to initiate work on others where we have only preliminary studies, such as the Notch receptor. The research involves protein expression, purification, characterisation of complexes, crystallisation, X-ray analysis and bioinformatics.