Regulation of neurexin 1β tertiary structure and ligand binding through alternative splicing

Neurexins and neuroligins play an essential role in synapse function, and their alterations are linked to autistic spectrum disorder. Interactions between neurexins and neuroligins regulate inhibitory and excitatory synaptogenesis in vitro through a "splice-insert signaling code." In particular, neurexin 10 carrying an alternative splice insert at site SS#4 interacts with neuroligin 2 (found predominantly at inhibitory synapses) but much less so with other neuroligins (those carrying an insert at site B and prevalent at excitatory synapses). The structure of neurexin 1 beta+SS#4 reveals dramatic rearrangements to the "hypervariable surface," the binding site for neuroligins. The splice insert protrudes as a long helix into space, triggers conversion of loop beta 10-beta 11 into a helix rearranging the binding site for neuroligins, and rearranges the Ca2+ -binding site required for ligand binding, increasing its affinity. Our structures reveal the mechanism by which neurexin 1 beta isoforms acquire neuroligin splice isoform selectivity.