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 (August 2017) Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins. Neuron, 95 (4). 896-913.e10. ISSN 0896-6273 (Public Dataset)
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: | 16 August 2017 |
| Date Deposited: | 18 Aug 2017 19:39 |
| Last Modified: | 21 Nov 2024 20:08 |
| PMCID: | PMC5625881 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/35246 |
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