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Structural Biology Programme

Cell Signalling and Adhesion Group

Group Leader:  Daniel Lietha
Research highlights

We showed that Focal adhesion Kinase (FAK) interacts with PIP lipids at cell adhesion sites and that this interaction induces FAK clustering and conformational changes, which trigger FAK autophosphorylation. Following this, Src is recruited to FAK and, in turn, phosphorylates the FAK kinase to induce full FAK activation. Currently, we are studying the architecture of FAK clusters bound to lipid membranes by electron microscopy, and we are investigating how force, induced at adhesion sites by 2 actomyosin contraction, induces changes to these structures in order 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. 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, and hence the rigid C2 interaction efficiently positions the active site towards its substrate (FIGURE). Although the C2 domain interacts with the phosphatase domain far from the active site, we show that the C2 interaction greatly enhances the catalytic activity 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. Furthermore, we confirmed via cell biology experiments that mutations at the domain interface affect downstream signalling to Akt.