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

Elegheert, Jonathan, Cvetkovska, Vedrana, Clayton, Amber J., Heroven, Christina, Vennekens, Kristel M., Smukowski, Samuel N., Regan, Michael C., Jia, Wanyi, Smith, Alexandra C., Furukawa, Hiro, Savas, Jeffrey N., de Wit, Joris, Begbie, Jo, Craig, Ann Marie, Aricescu, A. Radu (2017) Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins. Neuron, 95 (4). 896-913.e10. ISSN 0896-6273

URL: https://www.ncbi.nlm.nih.gov/pubmed/28817804
DOI: 10.1016/j.neuron.2017.07.040

Abstract

Summary 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.

Item Type: Paper
Uncontrolled Keywords: neurexin neuroligin MDGA synaptic organizer protein synaptic transmission autism spectrum disorder ASD
Subjects: diseases & disorders > mental disorders > personality disorders > autism
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > neurexin
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > synaptic transmission
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Matt Covey
Date Deposited: 18 Aug 2017 19:39
Last Modified: 06 Sep 2017 16:47
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Dataset ID:
URI: http://repository.cshl.edu/id/eprint/35246

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