Structure and organization of heteromeric AMPA-type glutamate receptors.
Structure and organization of heteromeric AMPA-type glutamate receptors.
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DOI：
10.1126/science.aad3873
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发表时间：
2016-04-29
期刊：
影响因子：
--
通讯作者：
Greger IH
中科院分区：
文献类型：
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作者：
Herguedas B;García-Nafría J;Cais O;Fernández-Leiro R;Krieger J;Ho H;Greger IH
AMPA型谷氨酸受体（AMPAR）是快速神经传递和突触可塑性的中枢介质，主要以GluA 1 -4亚基的异聚体形式存在。在这里，我们报告第一AMPAR异聚体结构，这大大偏离现有的GluA 2同聚体。GluA 2/3和GluA 2/4 N-末端结构域的晶体结构揭示了一种新的紧凑的构象，四个亚基围绕中心轴交替排列。这种组织被证实在全长受体的半胱氨酸交联，并允许我们确定一个完整的GluA 2/3受体的结构由冷冻电镜。在无配体状态下的两个模型，在8.25 μ m和10.3 μ m的分辨率，表现出实质性的垂直压缩和结构域层之间的密切联系，让人想起NMDA受体。模型1类似于静止状态，模型2是脱敏状态，在配体名义上不存在的情况下提供门控转换的快照。我们的数据揭示了异聚AMPAR的组织特征，并提供了一个框架来破译AMPAR的结构和信号。
AMPA-type glutamate receptors (AMPARs), central mediators of rapid neurotransmission and synaptic plasticity, predominantly exist as heteromers of the GluA1-4 subunits. Here we report first AMPAR heteromer structures, which deviate substantially from existing GluA2 homomers. Crystal structures of the GluA2/3 and GluA2/4 N-terminal domains reveal a novel compact conformation with an alternating arrangement of the four subunits around a central axis. This organization is confirmed by cysteine crosslinking in full-length receptors and permitted us to determine the structure of an intact GluA2/3 receptor by cryo-EM. Two models in the ligand-free state, at 8.25 Å and 10.3 Å resolution, exhibit a substantial vertical compression and close associations between domain layers, reminiscent of NMDA receptors. Model 1 resembles a resting state, model 2 a desensitized state, providing snapshots of gating transitions in the nominal absence of ligand. Our data reveal organizational features of heteromeric AMPARs and provide a framework to decipher AMPAR architecture and signaling.