Determining the molecular basis of disease-causing mutations in synaptic proteins.

Summary The Scott group interrogates the molecular mechanisms underlying cellular signalling and exploits these details to develop new tools for drug discovery. A key focus is on G protein-coupled receptors (GPCRs), the largest, yet potentially most underexploited class of drug targets. Our projects combine a wide range of methods such as: protein engineering, directed evolution, cell-based binding and signalling assays, lentivirus, X-ray crystallography, NMR, fluorescence microscopy, electron microscopy, computational modelling, and rational drug design.

Project Details

Sensory information from the environment is processed at the level of synapses, the most fundamental information-processing units in the nervous system. Vertebrate synapses contain large yet intricately organised signalling complexes comprising neurotransmitter receptors, scaffold proteins, transporters and cell adhesion proteins. Human genetic studies continue to increasingly highlight that disruption of pre- and postsynaptic proteins result in neurodevelopmental disorders. Here we are offering projects investigating the molecular basis of newly discovered disease-causing mutations in human presynaptic (with Sarah Gordon) and postsynaptic (with Jess Nithianantharajah) proteins.

We have found that several of these mutations alter the structure and function of the synaptic proteins, knowledge which not only informs us on protein function in normal cells, but may allow specific therapeutic targeting. Depending on the project students will be trained in: protein expression and purification, protein-protein interaction assays (FRET, BRET etc), protein thermostability measurements, X-ray crystallography, NMR and other biophysical methods, confocal microscopy, lentiviral transductions and have the potential to undertake in vivo and ex vivo experiments