Structural biology at the membrane interface is a largely uncharted territory. Electron Microscopy is the only technique that can image proteins in their natural environment. Understanding the molecular geometry of membrane complexes is essential, if we want to understand a wide range of cellular functions, from cancer to the formation of new connections in the brain.
First, we investigate the dynamics and structure of scaffolds that play a pivotal role in excitatory and inhibitory synapses. First described over 100 years ago, much has been learned about the general principles that underlie basic synapse function. However, untangling the structure of the complex intracellular protein interaction networks is an enormous challenge that has not noticeably advanced past the identification and basic functional characterization of the proteins that are involved. First we will focus on the synaptic scaffolding protein gephyrin, which is the major scaffolding protein organizing inhibitory synapses. Considering its crucial function in the inhibitory system, it is not surprising that Gephyrin has been identified in a wide range of mental diseases like autism or schizophrenia and a target for analgesic drugs.
Second, we are interested in the glycine receptor, which is the binding partner for gephyrin. This protein is not a passive binding partner for gephyrin but is getting modulated upon binding and is modified by itself. A complex of this core unit of the excitatory synapse has been elusive and a structure would open up a window into the dynamics of synaptic scaffolds and their regulation in diseases. Apart from the wealth of information gained by visualizing the gephyrin:glycine receptor complex, glycine receptors and their function is currently a ‘hot topic’. Recent studies identified them as a possible target for pain management. Therefore we target the receptor structure in different conformations and a physiologically relevant stoichiometry for facilitate the design of novel drugs.
Third, we just started collaborative work protein interacting with C kinase (PICK1), which is the major trafficking protein in the excitatory synapse. PICK1 is known to regulate a plethora of transmembrane proteins in and out of the synapse; from dopamine transporters to glutamate receptors. As such, PICK1 has evolved into a therapeutic target due to its role in virtually every major mental disease, like schizophrenia, drug addiction, epilepsy or Parkinson’s Disease. Obtaining a structure of this interesting protein in the context of the membrane will help us to devise novel therapies for the debilitating diseases this proteins is involved in