Architecture of fully occupied GluA2 AMPA receptor-TARP complex elucidated by cryo-EM.
Architecture of fully occupied GluA2 AMPA receptor-TARP complex elucidated by cryo-EM.
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DOI：
10.1038/nature18961
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发表时间：
2016-08-04
期刊：
影响因子：
64.8
通讯作者：
Gouaux E
中科院分区：
文献类型：
--
作者：
Zhao Y;Chen S;Yoshioka C;Baconguis I;Gouaux E
哺乳动物中枢神经系统中的快速兴奋性神经传递主要由 AMPA 敏感的离子型谷氨酸受体执行。 AMPA 受体位于谷氨酸能棘的突触后密度内，由与辅助亚基相关的异四聚体受体组件组成，其中最常见的是跨膜 AMPA 受体调节蛋白 (TARP)。 TARP 与 AMPA 受体的结合调节受体门控和药理学以及运输的动力学。在这里，我们报道了 TARP γ2 亚基饱和的同聚 GluA2 AMPA 受体的冷冻电镜结构，显示了 TARP 如何围绕离子通道域以四重对称排列，与 M1、M2 和 M4 TM 螺旋进行广泛的相互作用。一对 TARP 在双重对称配体结合域 (LBD)“蛤壳”下方像部分张开的“手”一样保持平衡，一对 TARP 并列靠近 LBD 二聚体界面，而另一对则靠近 LBD 二聚体-二聚体界面。 TARP 的胞外“结构域”不仅可以调节 LBD“蛤壳”闭合，还可以影响与受体激活和脱敏相关的 LBD 层构象重排，而 TARP 跨膜 (TM) 结构域支撑离子通道孔。
Fast excitatory neurotransmission in the mammalian central nervous system is largely carried out by AMPA-sensitive ionotropic glutamate receptors. Localized within the postsynaptic density of glutamatergic spines, AMPA receptors are composed of heterotetrameric receptor assemblies associated with auxiliary subunits, the most common of which are transmembrane AMPA-receptor regulatory proteins (TARPs). The association of TARPs with AMPA receptors modulates the kinetics of receptor gating and pharmacology, as well as trafficking. Here we report the cryo-EM structure of the homomeric GluA2 AMPA receptor saturated with TARP γ2 subunits, showing how the TARPs are arranged with four-fold symmetry around the ion channel domain, making extensive interactions with the M1, M2 and M4 TM helices. Poised like partially opened ‘hands’ underneath the two-fold symmetric ligand binding domain (LBD) ‘clamshells’, one pair of TARPs are juxtaposed near the LBD dimer interface, while the other pair is near the LBD dimer-dimer interface. The extracellular ‘domains’ of TARP are positioned to not only modulate LBD ‘clamshell’ closure, but also to affect conformational rearrangements of the LBD layer associated with receptor activation and desensitization, while the TARP transmembrane (TM) domains buttress the ion channel pore.