Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges

Neuroligins and neurexins promote synapse development and validation by forming trans-synaptic bridges spanning the synaptic cleft. Select pairs promote excitatory and inhibitory synapses, with neuroligin 2 (NLGN2) limited to inhibitory synapses and neuroligin 1 (NLGN1) dominating at excitatory synapses. The cell-surface molecules, MAM domain-containing glycosylphosphatidylinositol anchor 1 (MDGA1) and 2 (MDGA2), regulate trans-synaptic adhesion between neurexins and neuroligins, impacting NLGN2 and NLGN1, respectively. We have determined the molecular mechanism of MDGA action. MDGA1 Ig1-Ig2 is sufficient to bind NLGN2 with nanomolar affinity; its crystal structure reveals an unusual locked rod-shaped array. In the crystal structure of the complex, two MDGA1 Ig1-Ig2 molecules each span the entire NLGN2 dimer. Site-directed mutagenesis confirms the observed interaction interface. Strikingly, Ig1 from MDGA1 binds to the same region on NLGN2 as neurexins do. Thus, MDGAs regulate the formation of neuroligin-neurexin trans-synaptic bridges by sterically blocking access of neurexins to neuroligins. •The structure of MDGA1 Ig1-Ig2 and its complex with neuroligin 2 are determined•The rod-shaped MDGA1 Ig1-Ig2 array bridges an entire neuroligin 2 dimer•Key structural features of both proteins enable nanomolar affinity and selectivity•MDGA1 blocks neurexin binding on neuroligin 2, revealing its regulatory mechanism Neuroligins and neurexins form trans-synaptic bridges that promote synapse development; a third family of synaptic organizers, MDGAs, regulates these bridges. Gangwar et al. demonstrate the molecular mechanism underlying the regulatory action of MDGAs.