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

DOI: 10.1038/s41586-020-2498-z DOI Help

Authors: Ian J. Mcgough (The Francis Crick Institute) , Luca Vecchia (Wellcome Centre for Human Genetics, University of Oxford) , Benjamin Bishop (Wellcome Centre for Human Genetics, University of Oxford) , Tomas Malinauskas (The Wellcome Centre for Human Genetics, University of Oxford) , Karen Beckett (The Francis Crick Institute) , Dhira Joshi (The Francis Crick Institute) , Nicola O’reilly (The Francis Crick Institute) , Christian Siebold (Wellcome Centre for Human Genetics, University of Oxford) , E. Yvonne Jones (Wellcome Trust Centre for Human Genetics, University of Oxford) , Jean-Paul Vincent (The Francis Crick Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 423

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 19946

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 activity1,2,3. 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 problem4,5,6. 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.

Journal Keywords: Ectoderm; Morphogen signalling

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 29/07/2020 09:18

Discipline Tags:

Life Sciences & Biotech Biophysics Genetics Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)