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

Shanti Pal Gangwar, Xiaoying Zhong, Suchithra Seshadrinathan, Hui Chen, Mischa Machius, Gabby Rudenko

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)1132-1141.e4
JournalNeuron
Volume94
Issue number6
DOIs
StatePublished - Jun 21 2017

Keywords

  • MDGA
  • adhesion molecule
  • excitation-inhibition
  • neurexin
  • neuro-psychiatric disease
  • neuroligin
  • synapse development
  • synaptic organizer
  • synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

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    Gangwar, S. P., Zhong, X., Seshadrinathan, S., Chen, H., Machius, M., & Rudenko, G. (2017). Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges. Neuron, 94(6), 1132-1141.e4. https://doi.org/10.1016/j.neuron.2017.06.009