Molecular Mechanism of MDGA1

Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges

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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1132-1141
Number of pages10
JournalNeuron
Volume94
Issue number6
DOIs
StatePublished - Jun 21 2017

Fingerprint

Glycosylphosphatidylinositols
Synapses
Site-Directed Mutagenesis
neuroligin 2

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Molecular Mechanism of MDGA1 : Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges. / Gangwar, Shanti; Zhong, Xiaoying; Seshadrinathan, Suchithra; Chen, Hui; Machius, Mischa; Rudenko, Gabrielle.

In: Neuron, Vol. 94, No. 6, 21.06.2017, p. 1132-1141.

Research output: Contribution to journalArticle

Gangwar, S, Zhong, X, Seshadrinathan, S, Chen, H, Machius, M & Rudenko, G 2017, 'Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges', Neuron, vol. 94, no. 6, pp. 1132-1141. https://doi.org/10.1016/j.neuron.2017.06.009
Gangwar, Shanti ; Zhong, Xiaoying ; Seshadrinathan, Suchithra ; Chen, Hui ; Machius, Mischa ; Rudenko, Gabrielle. / Molecular Mechanism of MDGA1 : Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges. In: Neuron. 2017 ; Vol. 94, No. 6. pp. 1132-1141.
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