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Kakugawa, S., Langton, P.F., Zebisch, M., Howell, S.A., Chang, T.H., Liu, Y., Feizi, T., Bineva, G., O'Reilly, N., Snijders, A.P., Jones, E.Y., Vincent, J.P. (2015). Notum deacylates Wnt proteins to suppress signalling activity.  Nature 519(7542): 187--192.
FlyBase ID
FBrf0227813
Publication Type
Research paper
Abstract

Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase.

PubMed ID
PubMed Central ID
PMC4376489 (PMC) (EuropePMC)
Related Publication(s)
Note

Cell signalling: Disarming Wnt.
Nusse, 2015, Nature 519(7542): 163--164 [FBrf0228083]

Development: Switching off WNT with precision.
Baumann, 2015, Nat. Rev. Mol. Cell Biol. 16(4): 204 [FBrf0228357]

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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nature
    Title
    Nature
    Publication Year
    1869-
    ISBN/ISSN
    0028-0836
    Data From Reference