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研究揭示钙门控钾通道中的球链失活机制
作者:小柯机器人 发布时间:2020/3/24 15:04:58

美国威尔康奈尔医学院Crina M. Nimigean团队取得一项新进展,他们的最近研究揭示了钙门控钾通道中的球链失活机制。2020年3月18日,《自然》杂志在线发表了这项成果。

研究人员通过冷冻电镜从脂质环境中的嗜热自养甲烷菌获得MthK通道(一种纯钙门控和失活的通道)的结构,从而鉴定了钙激活钾通道的分子门控机理。在不存在Ca2+的情况下,研究人员获得了处于封闭状态的单个结构,通过原子模拟显示,该结构在环境温度下在脂双层中具有很高的柔性,门环的摇摆运动较大,而内衬螺旋的弯曲较大。在Ca2+结合的条件下,研究人员获得了几种结构,包括多个开放失活的构象,进一步表明了高动态蛋白。这些不同通道构象的特征是门控环相对于跨膜区域的摇摆,表明整个通道的对称性断裂。此外,在所有显示开放通道孔的构象中,通道四聚体的一个亚基的N末端会粘在孔中并堵塞孔,自由能模拟显示这是很强的相互作用。该N末端的缺失导致功能性非失活通道以及没有孔塞的开放状态结构,这表明该以往未解析的N端肽负责球链失活机制。
 
据介绍,失活是在开放刺激仍然存在的情况下,离子通道终止离子流从孔道通过的过程。在神经元中,钠离子通道和钾离子通道的失活对于动作电位的产生和发射频率的调节至关重要。通道或附属亚基的胞质结构域被认为可以通过“球链”机制堵塞开放孔,从而使通道失活。
 
附:英文原文

Title: Ball-and-chain inactivation in a calcium-gated potassium channel

Author: Chen Fan, Nattakan Sukomon, Emelie Flood, Jan Rheinberger, Toby W. Allen, Crina M. Nimigean

Issue&Volume: 2020-03-18

Abstract: Inactivation is the process by which ion channels terminate ion flux through their pores while the opening stimulus is still present1. In neurons, inactivation of both sodium and potassium channels is crucial for the generation of action potentials and regulation of firing frequency1,2. A cytoplasmic domain of either the channel or an accessory subunit is thought to plug the open pore to inactivate the channel via a ‘ball-and-chain’ mechanism3,4,5,6,7. Here we use cryo-electron microscopy to identify the molecular gating mechanism in calcium-activated potassium channels by obtaining structures of the MthK channel from Methanobacterium thermoautotrophicum—a purely calcium-gated and inactivating channel—in a lipid environment. In the absence of Ca2+, we obtained a single structure in a closed state, which was shown by atomistic simulations to be highly flexible in lipid bilayers at ambient temperature, with large rocking motions of the gating ring and bending of pore-lining helices. In Ca2+-bound conditions, we obtained several structures, including multiple open-inactivated conformations, further indication of a highly dynamic protein. These different channel conformations are distinguished by rocking of the gating rings with respect to the transmembrane region, indicating symmetry breakage across the channel. Furthermore, in all conformations displaying open channel pores, the N terminus of one subunit of the channel tetramer sticks into the pore and plugs it, with free energy simulations showing that this is a strong interaction. Deletion of this N terminus leads to functionally non-inactivating channels and structures of open states without a pore plug, indicating that this previously unresolved N-terminal peptide is responsible for a ball-and-chain inactivation mechanism.

DOI: 10.1038/s41586-020-2116-0

Source: https://www.nature.com/articles/s41586-020-2116-0

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html