Glypicans shield the Wnt lipid moiety to enable signalling at a distance

Ian J. McGough, Luca Vecchia, Benjamin Bishop, Tomas Malinauskas, Karen Beckett, Dhira Joshi, Nicola O’Reilly, Christian Siebold, E. Yvonne Jones () and Jean-Paul Vincent ()
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Ian J. McGough: The Francis Crick Institute
Luca Vecchia: University of Oxford
Benjamin Bishop: University of Oxford
Tomas Malinauskas: University of Oxford
Karen Beckett: The Francis Crick Institute
Dhira Joshi: The Francis Crick Institute
Nicola O’Reilly: The Francis Crick Institute
Christian Siebold: University of Oxford
E. Yvonne Jones: University of Oxford
Jean-Paul Vincent: The Francis Crick Institute

Nature, 2020, vol. 585, issue 7823, 85-90

Abstract: Abstract A relatively small number of proteins have been suggested to act as morphogens—signalling molecules that spread within tissues to organize tissue repair and the specification of cell fate during development. Among them are Wnt proteins, which carry a palmitoleate moiety that is essential for signalling activity1–3. How a hydrophobic lipoprotein can spread in the aqueous extracellular space is unknown. Several mechanisms, such as those involving lipoprotein particles, exosomes or a specific chaperone, have been proposed to overcome this so-called Wnt solubility problem4–6. Here we provide evidence against these models and show that the Wnt lipid is shielded by the core domain of a subclass of glypicans defined by the Dally-like protein (Dlp). Structural analysis shows that, in the presence of palmitoleoylated peptides, these glypicans change conformation to create a hydrophobic space. Thus, glypicans of the Dlp family protect the lipid of Wnt proteins from the aqueous environment and serve as a reservoir from which Wnt proteins can be handed over to signalling receptors.

Date: 2020
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DOI: 10.1038/s41586-020-2498-z

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