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

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.

DOI: 10.1016/j.neuron.2017.09.011

Cite this paper

@inproceedings{Elegheert2017StructuralMF, title={Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins}, author={Jonathan Elegheert and Vedrana Cvetkovska and Amber J. Clayton and Christina Heroven and Kristel M. Vennekens and Samuel N. Smukowski and Michael C. Regan and Wanyi Jia and Alexandra C. Smith and Hiro Furukawa and Jeffrey N Savas and Joris de Wit and Jo Begbie and Ann Marie Craig and A. Radu Aricescu}, booktitle={Neuron}, year={2017} }