Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins

Neuron. 2017 Aug 16;95(4):896-913.e10. doi: 10.1016/j.neuron.2017.07.040.


Neuroligin-neurexin (NL-NRX) complexes are fundamental synaptic organizers in the central nervous system. An accurate spatial and temporal control of NL-NRX signaling is crucial to balance excitatory and inhibitory neurotransmission, and perturbations are linked with neurodevelopmental and psychiatric disorders. MDGA proteins bind NLs and control their function and interaction with NRXs via unknown mechanisms. Here, we report crystal structures of MDGA1, the NL1-MDGA1 complex, and a spliced NL1 isoform. Two large, multi-domain MDGA molecules fold into rigid triangular structures, cradling a dimeric NL to prevent NRX binding. Structural analyses guided the discovery of a broad, splicing-modulated interaction network between MDGA and NL family members and helped rationalize the impact of autism-linked mutations. We demonstrate that expression levels largely determine whether MDGAs act selectively or suppress the synapse organizing function of multiple NLs. These results illustrate a potentially brain-wide regulatory mechanism for NL-NRX signaling modulation.

Keywords: ASD; MDGA; autism spectrum disorder; neurexin; neuroligin; synaptic organizer protein; synaptic transmission.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • COS Cells
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Chickens
  • Coculture Techniques
  • Dansyl Compounds / metabolism*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Galactosamine / analogs & derivatives*
  • Galactosamine / genetics
  • Galactosamine / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurturin / genetics
  • Neurturin / metabolism*
  • Protein Interaction Maps
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Sequence Alignment
  • Signal Transduction / physiology*
  • Synapses / physiology*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules, Neuronal
  • Dansyl Compounds
  • Extracellular Matrix Proteins
  • Membrane Proteins
  • NRTN protein, human
  • Nerve Tissue Proteins
  • Neurturin
  • Receptors, N-Methyl-D-Aspartate
  • SPARCL1 protein, human
  • SPZ1 protein, human
  • methyl-N-dansylgalactosaminide
  • Galactosamine