Gating mechanisms of acid-sensing ion channels,Nature

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Gating mechanisms of acid-sensing ion channels
Nature ( IF 50.5 ) Pub Date : 2018-03-01 , DOI: 10.1038/nature25782
Nate Yoder ₁ , Craig Yoshioka ₂ , Eric Gouaux _{1,

3}

Affiliation

Acid-sensing ion channels (ASICs) are trimeric, proton-gated and sodium-selective members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout vertebrate central and peripheral nervous systems. Gating of ASICs occurs on a millisecond time scale and the mechanism involves three conformational states: high pH resting, low pH open and low pH desensitized. Existing X-ray structures of ASIC1a describe the conformations of the open and desensitized states, but the structure of the high pH resting state and detailed mechanisms of the activation and desensitization of the channel have remained elusive. Here we present structures of the high pH resting state of homotrimeric chicken (Gallus gallus) ASIC1a, determined by X-ray crystallography and single particle cryo-electron microscopy, and present a comprehensive molecular mechanism for proton-dependent gating in ASICs. In the resting state, the position of the thumb domain is further from the three-fold molecular axis, thereby expanding the ‘acidic pocket’ in comparison to the open and desensitized states. Activation therefore involves ‘closure’ of the thumb into the acidic pocket, expansion of the lower palm domain and an iris-like opening of the channel gate. Furthermore, we demonstrate how the β11–β12 linkers that demarcate the upper and lower palm domains serve as a molecular ‘clutch’, and undergo a simple rearrangement to permit rapid desensitization.

中文翻译：

酸敏感离子通道的门控机制

酸敏感离子通道 (ASIC) 是上皮钠通道/退化蛋白 (ENaC/DEG) 离子通道超家族的三聚体、质子门控和钠选择性成员，在整个脊椎动物中枢和周围神经系统中均有表达。ASIC 的门控发生在毫秒时间尺度上，该机制涉及三种构象状态：高 pH 静止状态、低 pH 开放状态和低 pH 脱敏状态。ASIC1a 的现有 X 射线结构描述了开放和脱敏状态的构象，但高 pH 静息状态的结构以及通道激活和脱敏的详细机制仍然难以捉摸。在这里，我们展示了同源三聚体鸡 (Gallus gallus) ASIC1a 的高 pH 静息状态结构，由 X 射线晶体学和单粒子冷冻电子显微镜确定，并提出了 ASIC 中质子依赖门控的综合分子机制。在静息状态下，拇指区域的位置远离三重分子轴，从而与开放和脱敏状态相比扩大了“酸性口袋”。因此，激活涉及将拇指“关闭”到酸性口袋中、手掌下部区域的扩张以及通道门的虹膜样打开。此外，我们还展示了划分上下手掌结构域的 β11–β12 接头如何充当分子“离合器”，并进行简单的重排以允许快速脱敏。从而与开放和脱敏状态相比扩大了“酸性口袋”。因此，激活涉及将拇指“关闭”到酸性口袋中、手掌下部区域的扩张以及通道门的虹膜样打开。此外，我们还展示了划分上下手掌结构域的 β11–β12 接头如何充当分子“离合器”，并进行简单的重排以允许快速脱敏。从而与开放和脱敏状态相比扩大了“酸性口袋”。因此，激活涉及将拇指“关闭”到酸性口袋中、手掌下部区域的扩张以及通道门的虹膜样打开。此外，我们还展示了划分上下手掌结构域的 β11–β12 接头如何充当分子“离合器”，并进行简单的重排以允许快速脱敏。

更新日期：2018-03-01

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