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
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Neuron. 2017 Aug 16;95(4):896-913.e10. doi: 10.1016/j.neuron.2017.07.040.
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.
神经连接蛋白-神经突触素（NL-NRX）复合物是中枢神经系统中基本的突触组织者。对NL-NRX信号进行精确的时空控制对于平衡兴奋性和抑制性神经传递至关重要，而信号紊乱与神经发育和精神疾病有关。MDGA蛋白与神经连接蛋白结合，并通过未知机制控制其功能以及与神经突触素的相互作用。在此，我们报告了MDGA1、NL1-MDGA1复合物以及一种剪接的NL1异构体的晶体结构。两个大型多结构域MDGA分子折叠成刚性三角形结构，环抱二聚体神经连接蛋白以阻止神经突触素结合。结构分析引导发现了MDGA与神经连接蛋白家族成员之间广泛的、受剪接调节的相互作用网络，并有助于解释自闭症相关突变的影响。我们证明，表达水平在很大程度上决定了MDGA是选择性发挥作用还是抑制多种神经连接蛋白的突触组织功能。这些结果阐明了一种潜在的全脑范围的NL-NRX信号调节机制。
