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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Domain organization and function in GluK2 subtype kainate receptors
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Domain organization and function in GluK2 subtype kainate receptors

机译：GluK2亚型海藻酸盐受体中的域组织和功能

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摘要

Glutamate receptor ion channels (iGluRs) are excitatory neurotrans-mitter receptors with a unique molecular architecture in which the extracellular domains assemble as a dimer of dimers. The structure of individual dimer assemblies has been established previously for both the isolated ligand-binding domain (LBD) and more recently for the larger amino terminal domain (ATD). How these dimers pack to form tetrameric assemblies in intact iGluRs has remained controversial. Using recently solved crystal structures for the GluK2 kainate receptor ATD as a guide, we performed cysteine mutant cross-linking experiments in full-length tetrameric GluK2 to establish how the ATD packs in a dimer of dimers assembly. A similar approach, using a full-length AMPA receptor GluA2 crystal structure as a guide, was used to design cysteine mutant cross-links for the GluK2 LBD dimer of dimers assembly. The formation of cross-linked tetramers in full-length GluK2 by combinations of ATD and LBD mutants which individually produce only cross-linked dimers suggests that subunits in the ATD and LBD layers swap dimer partners. Functional studies reveal that cross-linking either the ATD or the LBD inhibits activation of GluK2 and that, in the LBD, cross-links within and between dimers have different effects. These results establish that kainate and AMPA receptors have a conserved extracellular architecture and provide insight into the role of individual dimer assemblies in activation of ion channel gating.
机译：谷氨酸受体离子通道（iGluRs）是具有独特分子结构的兴奋性神经递质受体，其中胞外域组装成二聚体的二聚体。先前已经为分离的配体结合域（LBD）建立了单个二聚体组装体的结构，并且最近已为较大的氨基末端域（ATD）建立了单个二聚体组装的结构。这些二聚体如何组装成完整的iGluRs形成四聚体组装仍存在争议。使用最近解决的GluK2海藻酸酯受体ATD的晶体结构作为指导，我们在全长四聚体GluK2中进行了半胱氨酸突变体交联实验，以确定ATD如何在二聚体组装的二聚体中堆积。使用全长AMPA受体GluA2晶体结构作为指导的类似方法，被用于设计二聚体GluK2 LBD二聚体的半胱氨酸突变体交联。通过分别仅产生交联二聚体的ATD和LBD突变体的组合在全长GluK2中形成交联四聚体，表明ATD和LBD层中的亚基交换二聚体伴侣。功能研究表明，ATD或LBD的交联会抑制GluK2的激活，而在LBD中，二聚体内部和之间的交联会产生不同的影响。这些结果表明，海藻酸盐和AMPA受体具有保守的细胞外结构，可洞察各个二聚体组件在激活离子通道门控中的作用。

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    Utpal Das; Janesh Kumar; Mark L. Mayer; Andrew J. R. Nested;

  • 作者单位

    Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892;

    rnLaboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892;

    rnLaboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892;

    rnLeibniz-Institut fuer Molekulare Pharmakologie, 13125 Berlin, Germany Neurocure, Charite-Universitaetsmedizin Berlin, 10117 Berlin, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    crystal structure; glutamate receptors; ligand gated ion channels;

    机译：晶体结构谷氨酸受体;配体门控离子通道;

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