Wide implications from discovery of enzyme that dampens an important class of signalling proteins

  • Date created: 26 February 2015

 

 

Wnts are signalling proteins with important and far-reaching roles, including controlling development, regeneration and stem cell maintenance.

Now researchers at the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute), the University of Oxford, CRUK and ICL have discovered an enzyme that dampens the activity of Wnts - providing a foundation for the development of chemicals that could be used to boost their activity, control stem cell behaviour and possibly even alleviate neurodegeneration.

Signalling by Wnt proteins is finely balanced to ensure normal development and healthy adulthood. Wnt proteins are characterised by the presence of a lipid that is added as they are made and is essential to their function.

Led by Dr Jean-Paul Vincent of NIMR and Yvonne Jones of Oxford, the scientists used a variety of disciplines - including Drosophila fruit fly genetics, biochemistry, biophysics, structure-function analysis, enzymology, peptide chemistry and mass spectroscopy - to investigate how Wnt proteins are regulated.

They discovered that an enzyme called Notum removes this lipid and reduces the signalling activity of the Wnt proteins.

The research also provides structural insight into how Notum recognises Wnts and shows how a surface protein called Glypicans contributes to this reaction. The paper is the first to describe the removal of a lipid from a protein outside a cell.

Dr Vincent said: "Our results provide the foundation to developing chemical inhibitors of Notum. Such inhibitors could be used to boost Wnt signalling within a physiologically relevant range, to control stem cell behaviour or to alleviate conditions associated with reduced signalling, such as neurodegeneration."

The paper, Notum deacylates Wnt proteins to suppress signalling activity, is published in Nature.

 

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