Download MendeleyStructures of neurexophilin-neurexin complexes reveal a regulatory mechanism of alternative splicing.
Wilson, S.C., White, K.I., Zhou, Q., Pfuetzner, R.A., Choi, U.B., Sudhof, T.C., Brunger, A.T.(2019) EMBO J 38: e101603-e101603
- PubMed: 31566781
- DOI: https://doi.org/10.15252/embj.2019101603
- Primary Citation of Related Structures:
6PNP, 6PNQ - PubMed Abstract:
Neurexins are presynaptic, cell-adhesion molecules that specify the functional properties of synapses via interactions with trans-synaptic ligands. Neurexins are extensively alternatively spliced at six canonical sites that regulate multifarious ligand interactions, but the structural mechanisms underlying alternative splicing-dependent neurexin regulation are largely unknown. Here, we determined high-resolution structures of the complex of neurexophilin-1 and the second laminin/neurexin/sex-hormone-binding globulin domain (LNS2) of neurexin-1 and examined how alternative splicing at splice site #2 (SS2) regulates the complex. Our data reveal a unique, extensive, neurexophilin-neurexin binding interface that extends the jelly-roll β-sandwich of LNS2 of neurexin-1 into neurexophilin-1. The SS2A insert of LNS2 augments this interface, increasing the binding affinity of LNS2 for neurexophilin-1. Taken together, our data reveal an unexpected architecture of neurexophilin-neurexin complexes that accounts for the modulation of binding by alternative splicing, which in turn regulates the competition of neurexophilin for neurexin binding with other ligands.
Organizational Affiliation:
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
