Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins.
Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins.
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DOI：
10.1016/j.neuron.2017.09.011
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发表时间：
2017-09-27
期刊：
影响因子：
16.2
通讯作者：
Aricescu AR
中科院分区：
文献类型：
--
作者：
Elegheert J;Cvetkovska V;Clayton AJ;Heroven C;Vennekens KM;Smukowski SN;Regan MC;Jia W;Smith AC;Furukawa H;Savas JN;de Wit J;Begbie J;Craig AM;Aricescu AR
神经胶质素-神经毒素（NL-NRX）复合物是中枢神经系统中基本的突触组织者。NL-NRX信号传导的准确空间和时间控制对于平衡兴奋性和抑制性神经传递至关重要，并且扰动与神经发育和精神疾病有关。MDGA蛋白结合NL并通过未知机制控制其功能和与NRX的相互作用。在这里，我们报告的晶体结构MDGA 1，NL 1-MDGA 1复合物，和剪接NL 1亚型。两个大的多结构域MDGA分子折叠成刚性三角形结构，支撑二聚体NL以防止NRX结合。结构分析指导了MDGA和NL家族成员之间广泛的剪接调节相互作用网络的发现，并帮助合理化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MDGAs是否选择性地发挥作用或抑制多个NLs的突触组织功能。这些结果说明了NL-NRX信号调节的潜在脑内调节机制。
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.
影响因子：
16.2
作者：
Elegheert J;Cvetkovska V;Clayton AJ;Heroven C;Vennekens KM;Smukowski SN;Regan MC;Jia W;Smith AC;Furukawa H;Savas JN;de Wit J;Begbie J;Craig AM;Aricescu AR
通讯作者：
Aricescu AR