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

DOI: 10.1016/j.neuron.2017.07.040 DOI Help

Authors: Jonathan Elegheert (Wellcome Trust Centre for Human Genetics, University of Oxford) , Vedrana Cvetkovska (Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia) , Amber J. Clayton (University Wellcome Trust Centre for Human Genetics, University of Oxfordof Oxford) , Christina Heroven (Wellcome Trust Centre for Human Genetics, University of Oxford; MRC Laboratory of Molecular Biology) , Kristel M. Vennekens (VIB Center for Brain and Disease Research; KU Leuven) , Samuel N. Smukowski (Northwestern University) , Michael C. Regan (Keck Structural Biology Laboratory) , Wanyi Jia (Wellcome Trust Centre for Human Genetics, University of Oxford) , Alexandra C. Smith (University of Oxford) , Hiro Furukawa (Keck Structural Biology Laboratory) , Jeffrey N. Savas (Northwestern University) , Joris De Wit (VIB Center for Brain and Disease Research; KU Leuven) , Jo Begbie (University of Oxford) , Ann Marie Craig (University of British Columbia) , Alexandru Aricescu (Wellcome Trust Centre for Human Genetics, University of Oxford; MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Neuron , VOL 95 , PAGES 896 - 913.e10

State: Published (Approved)
Published: August 2017
Diamond Proposal Number(s): 8423

Open Access Open Access

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.

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

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF

Documents:
1-s2.0-S0896627317306888-main.pdf