GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors
GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors
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GluA1 信号肽决定异聚 AMPA 受体的空间组装。
DOI：
10.1073/pnas.1524358113
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发表时间：
2016-09-20
影响因子：
11.1
通讯作者：
Shi, Yun Stone
中科院分区：
文献类型：
--
作者：
He, Xue-Yan;Li, Yan-Jun;Shi, Yun Stone
AMPA型谷氨酸受体（AMPAR）介导快速兴奋性神经传递，并主要在大脑中组装为异源四聚体。最近，同源四聚体GluA 2的晶体结构表明，AMPAR组装有两对构象不同的亚基，在二聚体的二聚体形成。然而，异聚AMPAR的结构仍不清楚。在GluA 2结构的指导下，我们在全长GluA 1/A2中进行了半胱氨酸突变体交联实验，旨在绘制异聚AMPAR结构。我们发现，氨基末端结构域决定了异源二聚体形成的第一个层次。当二聚体进一步组装成四聚体时，GluA 1和GluA 2亚基具有优选位置，具有1-2-1-2空间组装。通过交换关键序列，我们惊奇地发现空间组装模式由可切除的信号肽控制。用不相关的GluK 2信号肽替换表明GluA 1信号肽在确定空间优先级中起关键作用。因此，我们的研究揭示了一种重要类型的谷氨酸受体在大脑中的空间组装，并揭示了信号肽的新功能。
AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in fulllength GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1-2-1-2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides.