Wnt signalling, a critical pathway in embryogenesis and adult tissue homeostasis, orchestrates cell development, differentiation, and polarity. Dysregulation of this pathway underlies numerous cancers, including colorectal, breast, and pancreatic malignancies. My laboratory employs cryo-electron microscopy to elucidate key mechanisms within the Wnt signalling cascade.
Wnt signals are mediated by Frizzled G protein-coupled receptors (FZDs) in complex with co-receptors. We have determined high-resolution structures of activated FZD5 and FZD7 receptors in complex with G proteins, both in detergents and nanodiscs. Our findings suggest that FZD–G protein binding is mediated by a lipid molecule, a unique feature of all FZD receptors. We are working to identify this lipid through mass spectrometry and structural biology approaches. We hypothesise that lipids are integral to receptor–effector binding and play a direct role in FZD receptor activation and effector binding.
My laboratory’s interests extend to understanding the mechanisms of Wnt posttranslational modification, which is essential for its activity. We have determined the structure of Porcupine, a 55 kDa membrane-bound acyltransferase that modifies Wnts, enabling their secretion and biological activity, in its apo form and in complexes with high-affinity inhibitors C59 and LGK974 (the latter is in Phase II clinical trials). Our structural studies provide important insights into the mechanisms of ligand binding and inhibitor-induced conformational changes, potentially informing future therapeutic strategies.
This research not only advances our fundamental understanding of Wnt signalling but also unveils new strategies for therapeutic intervention.