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

25 February 2015

Wnt proteins are characterised by the presence of a lipid (palmitoleate), which is added during biosynthesis and is essential for their function. W

Image: Wnt proteins are characterised by the presence of a lipid (palmitoleate), which is added during biosynthesis and is essential for their function. Wnt activity is dampened by Notum, an inhibitor found in a wide range of multicellular organisms including humans. By combining Drosophila genetics with structural biology and other analytical techniques, the researchers found that Notum acts by removing the lipid from Wnt proteins thus rendering them inactive.

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.

 

  • Researchers have discovered an enzyme that dampens the activity of Wnt proteins. Wnts are a class of signalling proteins with functions in embryonic development, cell regeneration and stem cell maintenance - and have even been linked to cancer. 
  • Stem cells are immature cells that have not yet developed into the specialised cells that make up our organs and tissues. They have the ability to renew, or make identical copies of themselves, almost indefinitely.
  • The research was carried out by scientists from the Medical Research Council's National Institute for Medical Research, the University of Oxford, Imperial College London and Cancer Research UK's London Research Institute.