Understanding the extracellular distribution of the Wnt morphogen: the role of glypicans
The Wnt pathway represents a key embryonic morphogen signal, and a crucial regulator of tissue homeostasis and regeneration in the adult; dysregulation of its control leads to multiple degenerative and proliferative abnormalities, including several cancers. Molecularly, Wnts are lipid-modified proteins, and this modification is crucial for receptor engagement at the target cells; however, coupled with a complex folding, this hampers protein solubility during Wnt extracellular movement upstream of receptor activation. How then does Wnt overcome this “solubility problem”?
Solving the structure of the Drosophila melanogaster heparan-sulfate proteoglycan Dlp (Dally-like protein) in complex with a lipidated Wnt peptide, we showed that this class of membrane-anchored proteins, glypicans, have a key role in the extracellular shielding of the Wnt lipid. A conformational rearrangement takes place in the Dlp protein core, opening up a deep hydrophobic tunnel where the Wnt lipid can be buried. By biophysical analysis, we also demonstrated that the lipid-binding capacity is specific for a subset of glypicans. Coupled with mutational and in vivo experiments in flies in collaboration with the Vincent group at Francis Crick London, we confirmed that this interaction affects the extracellular spread of Wnt, highlighting the functional relevance of glypicans in the morphogen handover mechanism.