Structural basis for modulation of group III mGlu receptors by transsynaptic interactions

Group III metabotropic glutamate receptors (mGluRs) are critical signaling molecules that regulate strength, homeostasis, and plasticity of glutamatergic synaptic signaling. These receptors are engaged in transsynaptic interactions with extracellular leucine-rich repeat and fibronectin type III domain-containing (ELFN) cell adhesion proteins. ELFN proteins have been shown to play a critical role in regulation of activity and localization of mGluRs activity in vivo, yet the exact nature of their regulatory interaction has remained unknown. Here, we present a cryo-electron microscopy structure of the ELFN-mGluR complex. We identify a specific ELFN-binding pocket on mGluRs involved in its allosteric regulation through the network of residues affecting the orthosteric ligand binding site. We further uncover cooperativity whereby mGluR activation increases their association with ELFN proteins as a potential feedback mechanism to regulate synaptic strength. Last, we determine that disruption in mGluR-ELFN interaction is a recurring mechanism underlying several neurological conditions as we delineate their structure-functional etiology.