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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural determinants of ion permeation in CRAC channels
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Structural determinants of ion permeation in CRAC channels

机译：CRAC通道中离子渗透的结构决定因素

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摘要

CRAC channels generate Ca~(2+) signals critical for the activation of immune cells and exhibit an intriguing pore profile distinguished by extremely high Ca~(2+) selectivity, low Cs~+ permeability, and small unitary conductance. To identify the ion conduction pathway and gain insight into the structural bases of these permeation characteristics, we introduced cysteine residues in the CRAC channel pore subunit, Orai1, and probed their accessibility to various thiol-reactive reagents. Our results indicate that the architecture of the ion conduction pathway is characterized by a flexible outer vestibule formed by the TM1-TM2 loop, which leads to a narrow pore flanked by residues of a helical TM1 segment. Residues in TM3, and specifically, E190, a residue considered important for ion selectivity, are not close to the pore. Moreover, the outer vestibule does not significantly contribute to ion selectivity, implying that Ca~(2+) selectivity is conferred mainly by E106. The ion conduction pathway is sufficiently narrow along much of its length to permit stable coordination of Cd~(2+) by several TM1 residues, which likely explains the slow flux of ions within the restrained geometry of the pore. These results provide a structural framework to understand the unique permeation properties of CRAC channels.
机译：CRAC通道产生对免疫细胞活化至关重要的Ca〜（2+）信号，并表现出令人感兴趣的孔特征，其具有极高的Ca〜（2+）选择性，低Cs〜+渗透性和小的单位电导率。为了确定离子传导途径并深入了解这些渗透特征的结构基础，我们在CRAC通道孔亚基Orai1中引入了半胱氨酸残基，并探讨了它们与各种硫醇反应试剂的可及性。我们的结果表明，离子传导途径的结构特征是由TM1-TM2环形成的柔性外部前庭，这导致了一个狭窄的孔，两侧是螺旋TM1段的残基。 TM3中的残基，特别是E190（认为对离子选择性很重要的残基）不靠近孔。此外，外部前庭对离子选择性没有显着贡献，这表明Ca〜（2+）选择性主要由E106赋予。离子传导路径在其大部分长度上都足够狭窄，以允许Cd〜（2+）被多个TM1残基稳定配位，这很可能解释了离子在受约束的孔内的缓慢流动。这些结果提供了一个结构框架，以了解CRAC通道的独特渗透特性。

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  • 作者

    Beth A. McNally; Megumi Yamashita; Anita Engh; Murali Prakriya;

  • 作者单位

    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University School of Medicine, Chicago, IL 60611;

    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University School of Medicine, Chicago, IL 60611;

    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University School of Medicine, Chicago, IL 60611;

    Department of Molecular Pharmacology and Biological Chemistry, Northwestern University School of Medicine, Chicago, IL 60611;

  • 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

    Orai1; STIM1; store-operated channels;

    机译：Orai1;STIM1;商店经营的渠道;

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