Supra-molecular organization and function of ionotropic glutamate receptors

Excitatory neurotransmission at chemical synapses in the vertebrate central nervous system is largely mediated by ionotropic glutamate receptors (iGluRs). All iGluRs are assembled from four multi-domain core subunits, which harbour binding sites for agonists and allosteric modulators and delineate a central ion channel pore across the neuronal plasma membrane. From a mechanistic point of view, the study of iGluRs has reached a very exciting stage. A series of full-length receptor structures, aided by an integrated analysis combining single-particle cryo-electron microscopy, X-ray crystallography and electrophysiology, have started to define most states of the iGluR gating cycle at intermediate resolution.

However, it is increasingly clear that, at neuronal synapses, these channels do not exist or function in isolation. The core iGluR subunits are embedded into supramolecular assemblies that include multiple extracellular, transmembrane and intracellular proteins beyond the four core subunits. Such complexes are known to modulate receptor trafficking and signalling, but in most cases a structure-based, mechanistic understanding of these processes is lacking.

This project will focus on the structural and functional analysis of iGluR complexes with extracellular proteins, spanning the synaptic cleft, building up on the ongoing collaboration between the groups of Ingo Greger and Radu Aricescu. Multiple options are available, centered around AMPA and kainate iGluR sub-families. This is an excellent opportunity to acquire training in human membrane protein structural biology, including single-particle cryo-EM and X-ray crystallography, combined with biophysical analyses, electrophysiology and super-resolution fluorescence microscopy.