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.2017.07.040
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发表时间：
2017-08-16
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
神经连接蛋白-神经红素(NL-NRX)复合体是中枢神经系统中基本的突触组织者。准确的时空控制NL-NRX信号对于平衡兴奋性和抑制性神经传递是至关重要的，而神经发育和精神障碍与扰动有关。MDGA蛋白通过未知的机制与NLS结合并控制其功能和与NRXs的相互作用。在这里，我们报告了MDGA1、NL1-MDGA1复合体和拼接的NL1异构体的晶体结构。两个大的多域MDGA分子折叠成刚性的三角形结构，怀抱着一个二聚体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，并帮助合理地解释了自闭症相关突变的影响。我们证明，MDGA的表达水平在很大程度上决定了MDGA是选择性地作用于还是抑制多个NL的突触组织功能。这些结果说明了NL-NRX信号调制的一种潜在的全脑调控机制。MDGA1胞外区具有不寻常的三角形多域排列NL1-MDGA1复合体结构揭示了MDGA蛋白如何阻止Neuresin结合MDGA1和MDGA2结合所有NL亚型，这一过程通过交替剪接MDGA1和MDGA2以浓度依赖的方式抑制NL突触发生活性。介绍了自闭症相关突触后蛋白MDGA与突触组织者神经连接素的复合体的晶体结构，为MDGA蛋白对突触神经连接素-neuresin信号的潜在脑范围调控提供了结构和机制基础。
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. The MDGA1 extracellular region has an unusual triangular multi-domain arrangement The NL1-MDGA1 complex structure reveals how MDGA proteins block neurexin binding MDGA1 and MDGA2 bind all NL isoforms, a process fine-tuned by alternative splicing MDGA1 and MDGA2 suppress NL synaptogenic activity in a concentration-dependent manner Elegheert et al. present the crystal structure of the autism-linked post-synaptic protein MDGA in complex with the synapse organizer neuroligin, providing a structural and mechanistic basis for potentially brain-wide modulation of synaptic neuroligin-neurexin signaling by MDGA proteins.
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影响因子：
3.5
作者：
Chih, B;Afridi, SK;Scheiffele, P
通讯作者：
Scheiffele, P
影响因子：
15.9
作者：
Bemben, Michael A.;Shipman, Seth L.;Nicoll, Roger A.;Roche, Katherine W.
通讯作者：
Roche, Katherine W.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
4.8
作者：
Comoletti, D;Flynn, R;Taylor, P
通讯作者：
Taylor, P
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC