Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins
Neuron. 2017-08-01; 95(4): 896-913.e10
DOI: 10.1016/j.neuron.2017.07.040
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Elegheert J(1), Cvetkovska V(2), Clayton AJ(3), Heroven C(4), Vennekens KM(5), Smukowski SN(6), Regan MC(7), Jia W(3), Smith AC(8), Furukawa H(7), Savas JN(6), de Wit J(5), Begbie J(8), Craig AM(9), Aricescu AR(10).
Author information:
(1) Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
(2) Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
(3) Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
(4) Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
(5) VIB Center for Brain and Disease Research, Herestraat 49, B-3000 Leuven, Belgium; Department of Neurosciences, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
(6) Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
(7) Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
(8) Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
(9) Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
(10) Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
Erratum in
Neuron. 2017 Sep 27;96(1):242-244.
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.