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Structural basis of kainate subtype glutamate receptor desensitization

机译：红藻氨酸型谷氨酸受体脱敏的结构基础

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摘要

Glutamate receptors are ligand-gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction underlies diverse diseases(1,2). In both the resting and desensitized states of AMPA and kainate receptor subtypes, the ion channels are closed, whereas the ligand-binding domains, which are physically coupled to the channels, adopt markedly different conformations(3-6). Without an atomic model for the desensitized state, it is not possible to address a central problem in receptor gating: how the resting and desensitized receptor states both display closed ion channels, although they have major differences in the quaternary structure of the ligand-binding domain. Here, by determining the structure of the kainate receptor GluK2 subtype in its desensitized state by cryo-electron microscopy (cryo-EM) at 3.8 angstrom resolution, we show that desensitization is characterized by the establishment of a ringlike structure in the ligand-binding domain layer of the receptor. Formation of this 'desensitization ring' is mediated by staggered helix contacts between adjacent subunits, which leads to a pseudo-four-fold symmetric arrangement of the ligand-binding domains, illustrating subtle changes in symmetry that are important for the gating mechanism. Disruption of the desensitization ring is probably the key switch that enables restoration of the receptor to its resting state, thereby completing the gating cycle.
机译：谷氨酸受体是在中枢神经系统中介导突触传递的配体门控四聚离子通道。它们在脊椎动物的认知中起着重要作用，其功能障碍是多种疾病的基础（1,2）。在AMPA和红藻氨酸受体亚型的静止和脱敏状态下，离子通道都是封闭的，而与通道物理偶联的配体结合域则具有明显不同的构型（3-6）。没有脱敏状态的原子模型，就不可能解决受体门控中的核心问题：静止和脱敏受体状态如何都显示封闭的离子通道，尽管它们在配体结合域的四级结构上有很大差异。在这里，通过以3.8埃分辨率通过冷冻电子显微镜（cryo-EM）确定脱敏状态的海藻酸酯受体GluK2亚型的结构，我们表明脱敏的特征在于在配体结合域中建立了环状结构受体层。此“脱敏环”的形成是由相邻亚基之间交错的螺旋接触介导的，这导致配体结合域的伪四重对称排列，说明了对门控机制很重要的对称性细微变化。脱敏环的破坏可能是使受体恢复到其静止状态从而完成门控周期的关键开关。

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  • 来源
    《Nature》 |2016年第7621期|567-571|共5页
  • 作者

    Meyerson Joel R.; Chittori Sagar; Merk Alan; Rao Prashant; Han Tae Hee; Serpe Mihaela; Mayer Mark L.; Subramaniam Sriram;

  • 作者单位

    NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA|Brandeis Univ, Howard Hughes Med Inst, Dept Biochem, Waltham, MA 02454 USA;

    NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA|NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA;

    NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA;

    NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA;

    NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA;

    NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA;

    NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA;

    NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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