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Structures and pH-sensing mechanism of the proton-activated chloride channel

机译：质子活性氯化物通道的结构和pH传感机制

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摘要

The proton-activated chloride channel (PAC) is active across a wide range of mammalian cells and is involved in acid-induced cell death and tissue injury(1-3). PAC has recently been shown to represent a novel and evolutionarily conserved protein family(4,5). Here we present two cryo-electron microscopy structures of human PAC in a high-pH resting closed state and a low-pH proton-bound non-conducting state. PAC is a trimer in which each subunit consists of a transmembrane domain (TMD), which is formed of two helices (TM1 and TM2), and an extracellular domain (ECD). Upon a decrease of pH from 8 to 4, we observed marked conformational changes in the ECD-TMD interface and the TMD. The rearrangement of the ECD-TMD interface is characterized by the movement of the histidine 98 residue, which is, after acidification, decoupled from the resting position and inserted into an acidic pocket that is about 5 angstrom away. Within the TMD, TM1 undergoes a rotational movement, switching its interaction partner from its cognate TM2 to the adjacent TM2. The anion selectivity of PAC is determined by the positively charged lysine 319 residue on TM2, and replacing lysine 319 with a glutamate residue converts PAC to a cation-selective channel. Our data provide a glimpse of the molecular assembly of PAC, and a basis for understanding the mechanism of proton-dependent activation.Cryo-electron microscopy structures of the human proton-activated chloride channel (PAC) shed light on its pH-dependent gating mechanism and anion selectivity.
机译：质子活性氯化物通道（PAC）横跨各种哺乳动物细胞活性，并参与酸性诱导的细胞死亡和组织损伤（1-3）。 PAC最近已被证明代表了一种新颖和进化的保守蛋白质（4,5）。在这里，我们在高pH静置闭合状态和低pH质子结合的非导电状态下呈现人PAC的两种冷冻电子显微镜结构。 PAC是一个三聚体，其中每个亚基由跨膜结构域（TMD）组成，其由两个螺旋（TM1和TM2）和细胞外结构域（ECD）形成。在8至4的pH值下降时，我们观察到ECD-TMD接口和TMD的标记构象变化。 ECD-TMD界面的重新排列的特征在于组氨酸98残基的运动，即酸化，从静止位置分离并插入约5埃的酸性口袋中。在TMD内，TM1经历旋转运动，将其与其对相邻TM2的相互作用伙伴切换到相邻TM2。 PAC的阴离子选择性由TM2上的带正电荷的赖氨酸319残基确定，用谷氨酸残基替换赖氨酸319将PAC转化为阳离子选择性通道。我们的数据提供了PAC的分子组合的一瞥，理解质子依赖性活化机制的基础。人质子活性氯通道（PAC）脱光在其pH依赖性门控机构上的克罗莫 - 电子显微镜结构和阴离子选择性。

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  • 来源
    《Nature》 |2020年第7837期|350-354|共5页
  • 作者

    Ruan Zheng; Osei-Owusu James; Du Juan; Qiu Zhaozhu; Lu Wei;

  • 作者单位

    Van Andel Inst Dept Struct Biol Grand Rapids MI 49503 USA;

    Johns Hopkins Univ Sch Med Dept Physiol Baltimore MD 21205 USA;

    Van Andel Inst Dept Struct Biol Grand Rapids MI 49503 USA;

    Johns Hopkins Univ Sch Med Dept Physiol Baltimore MD 21205 USA|Johns Hopkins Univ Sch Med Solomon H Snyder Dept Neurosci Baltimore MD 21205 USA;

    Van Andel Inst Dept Struct Biol Grand Rapids MI 49503 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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