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Structural Biology Programme

Cell Signalling and Adhesion Group

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Research highlights

We discovered that Focal Adhesion Kinase (FAK) interacts with PIP2 lipids at cell adhesion sites and that this induces formation of large FAK oligomers on the membrane. This triggers conformational changes in FAK resulting in FAK autophosphorylation, Src recruitment and, in turn, full FAK activation via phosphorylation by Src. Currently, we are studying the atomic architecture of FAK oligomers bound to lipid membranes by electron microscopy, and are investigating how force, induced at focal adhesion sites by actomyosin contraction, induces changes to these structures to activate focal adhesion signalling. We utilise these mechanistic insights to discover highly specific allosteric FAK inhibitors. We employ experimental and virtual screening using fragment based approaches to identify allosteric ligands, and then use a structure based approach to develop these fragments into inhibitory lead compounds.

SH2-domain-containing inositol 5-phosphatases (SHIP) remove the 5-phosphate from PIP3 and thereby, like PTEN, negatively regulate PIP3 levels in the plasma membrane. Despite their importance, little is known about the mechanisms of SHIP regulation. We solved a crystal structure containing the catalytic and C2 domains of SHIP2, showing an extensive interface between the two domains. We have shown that the C2 domain of SHIP2 binds phosphatidylserine (PtdSer), which positions the active site towards its membrane substrate for increased catalytic efficiency (FIGURE). In addition, although the C2 domain interacts far from the active site, we have found that the C2 allosterically induces strong catalytic activation of SHIP2. We employed molecular dynamics simulations to guide a mutagenesis study that has identified distinct allosteric signalling pathways emanating from hydrophobic or polar interdomain interactions, which differentially affect lipid chain or head group regions of the substrate. In addition, through cell biology experiments, we have confirmed that mutations at the domain interface affect downstream signalling to Akt.