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 (FZD) G protein-coupled receptors (GPCRs) 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. Determined in the absence of ligands, these complexes present an enigma of how FZD receptor activation leads to G protein engagement and what events might regulate this process. Adding to this puzzle is an unusual, compared to other GPCRs, mode of G protein binding by FZD receptors. My laboratory is trying to understand what these unusual structural features mean for FZD receptor activation and signalling and how these insights can be used for drug design purposes.