Skip to Content
MilliporeSigma
  • Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins.

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

Neuron (2017-08-18)
Jonathan Elegheert, Vedrana Cvetkovska, Amber J Clayton, Christina Heroven, Kristel M Vennekens, Samuel N Smukowski, Michael C Regan, Wanyi Jia, Alexandra C Smith, Hiro Furukawa, Jeffrey N Savas, Joris de Wit, Jo Begbie, Ann Marie Craig, A Radu Aricescu
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Tau-1 Antibody, clone PC1C6, clone PC1C6, Chemicon®, from mouse
Sigma-Aldrich
Seleno-L-methionine, ≥98% (TLC), powder
Sigma-Aldrich
Bovine Serum Albumin, lyophilized powder, essentially globulin free, ≥99% (agarose gel electrophoresis)
Sigma-Aldrich
Anti-c-Myc antibody produced in rabbit, ~0.5 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
N-Methyl-D-aspartic acid, ≥98% (TLC), solid
Sigma-Aldrich
Polyethylenimine, branched, average Mw ~25,000 by LS, average Mn ~10,000 by GPC, branched
Sigma-Aldrich
Streptavidin from Streptomyces avidinii, essentially salt-free, lyophilized powder, ≥13 units/mg protein