A variety of signalling molecules ensure that the process of development from an undifferentiated ball of cells to an adult of the right size and shape proceeds according to plan. Matthias Zebisch at the Structural Biology Division (STRUBI) in WTCHG, working with STRUBI co-head Yvonne Jones and other colleagues in Oxford and Jean-Paul Vincent’s group at the National Institute of Medical Resarch in Mill Hill, has discovered a unique feedback mechanism that controls one of the most important of these molecules. The result could have implications for the treatment of diseases including cancer and Alzheimer’s disease.
The Wnt family of signalling molecules are found in every animal species, from worms to humans. They are proteins secreted from cells that guide the development of front-to-back and top-to-bottom axes, the differentiation of cells, and their proliferation and migration, and so are essential for life. However, excessive Wnt signalling has been association with cancer, and the body has a complicated set of feedback networks to ensure that it remains in balance.
One negative feedback circuit is mediated by another protein called Notum, released by cells when Wnt binds to the receptor on the cell membrane. Until now, researchers believed that Notum worked by modifying molecules called glypicans that help Wnt to attach to the membrane before it interacts with its receptor. But the research team carried out a number of experiments showing that Notum’s effects on Wnt were too specific to be mediated via the glypicans, which participate in several other molecular interactions.
Now Zebisch and his colleagues have solved the three-dimensional structure of Notum, revealing a deep ‘pocket’ that pointed to its direct action on Wnt. Notum also binds to glypicans alongside Wnt, putting itself in a position to modify the signalling molecule by trapping in its ‘pocket’ a fatty acid chain Wnt needs to interact with its receptor, and snipping it off. The team found that Notum makes the cut at an acyl group: it is therefore the kind of enzyme known as a deacylase.
‘Notum is the first enzyme known to deacylate an extracellular protein’, says Matthias Zebisch, ‘and our results suggest that it only acts on members of the Wnt family. Our study illustrates that if there is a mechanism that can be used to regulate the signalling activity of the very fundamental Wnt proteins, Nature has almost certainly found it.’
The team suggests that drugs could be targeted at Notum to block its activity in conditions where Wnt is underactive, such as. in ageing bone or neurodegenerative diseases, or alternatively that recombinant Notum could be used as a therapy against excess Wnt signalling in cancer.