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How does the brain work?
This is one of the most fundamental and difficult questions a human can ask. There are many layers to it, philosophical as well as scientific. My scientific interest lies in particular proteins on the surface of brain cells. Much like a navigation system, these proteins are able to direct brain cells along the right paths. They also help them form connections to other brain cells and thereby give rise to complex neural networks. Currently, I am working on two specific types of proteins and their binding partners, the ephrins and the netrins.
The ephrins bind to a large family of cell surface proteins, called the Eph receptors. When ephrin binds, Eph receptors crowd together to form large assemblies. I am interested in the molecular architecture of these assemblies (Seiradake et al., NSMB, 2010). My most recent work shows that ephrin can send either a ”stay” or a ”go” signal. Which of the two signals is sent depends on the type of Eph receptor present. I used X-ray crystallography and various biophysical and cell biology techniques to understand how the two different signals are initiated. This exciting work provides a glimpse into how cells choose between adhering to stay where they are and moving on (Seiradake et al., NSMB, 2013).
NetrinG1 and G2 work differently. As far as we know, they each bind strongly only to one partner. NetrinG1 binds to NGL1 and NetrinG2 binds to NGL2. They can thereby selectively fish out their specific NGL binding partners and trap them in different layers of the brain. This sorting process contributes to keeping the brain layers intact and influences the type of neuronal connections formed. I studied the crystal structures of NetrinGs and NGLs to understand how they recognise each other. I then used the information to engineer NGL proteins with ”swapped” binding preferences, in effect turning the sorting system upside down (Seiradake et al., EMBO J., 2011). These engineered NGLs are now used by other labs to further understand the function of these proteins.