2. Academic Validation
  3. Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges

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

  • Neuron. 2017 Jun 21;94(6):1132-1141.e4. doi: 10.1016/j.neuron.2017.06.009.
Shanti Pal Gangwar 1,  Xiaoying Zhong 1,  Suchithra Seshadrinathan 1,  Hui Chen 2,  Mischa Machius 1,  Gabby Rudenko 3
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 2 University of Michigan, Ann Arbor, MI 48109, USA.
  • 3 Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: garudenk@utmb.edu.
PMID: 28641112 DOI: 10.1016/j.neuron.2017.06.009
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.

Keywords

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

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