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Notum deacylates Wnt proteins to suppress signalling activity

DOI: 10.1038/nature14259 DOI Help
PMID: 25731175 PMID Help

Authors: Satoshi Kakugawa (MRC's National Institute for Medical Research) , Paul F. Langton (MRC's National Institute for Medical Research) , Matthias Zebisch (Wellcome Trust Centre for Human Genetics, University of Oxford) , Steven A. Howell (MRC's National Institute for Medical Research) , Tao-Hsin Chang (Wellcome Trust Centre for Human Genetics, University of Oxford) , Yan Liu (Imperial College London) , Ten Feizi (Imperial College London) , Ganka Bineva (Cancer Research UK) , Nicola O'Reilly (Cancer Research UK) , Ambrosius P. Snijders (Cancer Research UK) , E. Yvonne Jones (Wellcome Trust Centre for Human Genetics, University of Oxford) , Jean-Paul Vincent (MRC's National Institute for Medical Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 519 (7542) , PAGES 187 - 192

State: Published (Approved)
Published: February 2015
Diamond Proposal Number(s): 8423

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.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 27/03/2015 14:08

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)