Structural basis for integration of GluD receptors within synaptic organizer complexes.
Structural basis for integration of GluD receptors within synaptic organizer complexes.
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DOI：
10.1126/science.aae0104
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发表时间：
2016-07-15
期刊：
影响因子：
--
通讯作者：
Aricescu AR
中科院分区：
文献类型：
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作者：
Elegheert J;Kakegawa W;Clay JE;Shanks NF;Behiels E;Matsuda K;Kohda K;Miura E;Rossmann M;Mitakidis N;Motohashi J;Chang VT;Siebold C;Greger IH;Nakagawa T;Yuzaki M;Aricescu AR
离子型谷氨酸受体家族成员（iGluRs）整合到超分子复合物中，调节它们在兴奋性突触中的位置和功能。然而，目前缺乏分离的受体或其片段以外的结构信息限制了对生理iGluR信号传导的机制理解。在这里，我们报告了通过C1 q样突触组织者Cbln 1连接突触后iGluR δ2（GluD 2）和突触前β-neurexin-1（β-NRX 1）的原型分子桥的结构和功能分析。我们展示了Cbln 1六聚体如何“锚”GluD 2氨基末端结构域二聚体与单体β-NRX 1。这种排列促进突触发生，并且是体内D-丝氨酸依赖性GluD 2信号传导所必需的，是发育中小鼠小脑平行纤维-浦肯野细胞（PF-PC）突触和运动协调的长期抑制的基础。这些结果导致蛋白质和小分子配体协同控制突触iGluR功能的模型。
Ionotropic glutamate receptor family members (iGluRs) are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking post-synaptic iGluR δ2 (GluD2) and pre-synaptic β-neurexin-1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer. We show how Cbln1 hexamers “anchor” GluD2 amino-terminal domain dimers to monomeric β-NRX1. This arrangement promotes synaptogenesis, and is essential for D-Serine-dependent GluD2 signaling in vivo, underlying long-term depression of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses and motor coordination in developing mice. These results lead to a model where protein and small-molecule ligands synergistically control synaptic iGluR function.