Signal transduction of the GPCR Smoothened: a key protein in Hedgehog-regulated morphogenesis and oncogenesis (360G-Wellcome-203726_Z_16_A)

In complex multicellular organisms, cell-to-cell communication is often managed by morphogen gradients. The secreted Hedgehog ligands fall within this class, as they act in this manner during embryonic development. The Hedgehog signalling pathway (stimulated by these morphogens) tightly regulates crucial developmental processes including body patterning and symmetry. Serious developmental disorders result from inactivation of this pathway during embryogenesis, including holoprosencephaly and cyclopia. Hedgehog signalling is also active through stem cell programs throughout adult life, and aberrant Hedgehog activation, either ligand dependent or mutations in pathway components, can lead to cancer including medulloblastoma and basal cell carcinoma. The G-protein coupled receptor (GPCR) Smoothened is a key protein of this pathway, as it initiates the intracellular cascade, and is already targeted by anti-cancer drugs including Vismodegib and Sonidegib. However, the mechanism of signal transduction has only been poorly characterised. This project aims to explore this using both structural and biophysical approaches. We will study the mechanism and interplay of the two identified ligand-binding sites and the dynamics of agonist association with Smoothened. The ultimate goal is to determine the structure of active-state Smoothened and hence describe the mechanism by which its signal is transmitted across the plasma membrane.