Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel.
Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel.
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DOI：
10.1016/j.str.2017.03.006
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发表时间：
2017-05-02
期刊：
影响因子：
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通讯作者：
Tucker SJ
中科院分区：
文献类型：
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作者：
Aryal P;Jarerattanachat V;Clausen MV;Schewe M;McClenaghan C;Argent L;Conrad LJ;Dong YY;Pike ACW;Carpenter EP;Baukrowitz T;Sansom MSP;Tucker SJ
机械敏感性双孔结构域（K2P）K+通道（TREK-1、TREK-2和TRAAK）对于机械和热伤害感受是重要的。然而，其门控膜拉伸的机制仍然存在争议。在这里，我们使用分子动力学模拟来研究它们在脂质双层中的行为。我们表明，TREK-2移动从“向下”到“向上”的构象在直接响应膜拉伸，并检查在这个过程中的跨膜压力分布的作用。此外，我们展示了与脂质的状态依赖性相互作用如何影响TREK-2的运动，以及拉伸如何影响内孔和选择性过滤器。最后，我们提出的功能研究，证明了为什么直接孔块脂质尾巴不代表机械的主要机制。总的来说，这项研究提供了一个动态的结构洞察K2P通道mechanosensitivity，并说明了真核mechanosensitive离子通道的结构如何响应双层内的力的变化。TREK-2的机械门控涉及从下到上构象的运动模拟样品广泛的机械敏感性K2P通道结构的压力分布和状态依赖性脂质相互作用的变化起着关键作用内孔的脂质阻断不介导拉伸激活Aryal et al.使用MD模拟来了解机械敏感性K2 P通道TREK-2的牵张激活。他们展示了双层内力的变化如何驱动不同构象之间的运动，并研究了脂质在这一过程中发挥的作用。
The mechanosensitive two-pore domain (K2P) K+ channels (TREK-1, TREK-2, and TRAAK) are important for mechanical and thermal nociception. However, the mechanisms underlying their gating by membrane stretch remain controversial. Here we use molecular dynamics simulations to examine their behavior in a lipid bilayer. We show that TREK-2 moves from the “down” to “up” conformation in direct response to membrane stretch, and examine the role of the transmembrane pressure profile in this process. Furthermore, we show how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. Finally, we present functional studies that demonstrate why direct pore block by lipid tails does not represent the principal mechanism of mechanogating. Overall, this study provides a dynamic structural insight into K2P channel mechanosensitivity and illustrates how the structure of a eukaryotic mechanosensitive ion channel responds to changes in forces within the bilayer. Mechanogating of TREK-2 involves movement from the down to up conformation Simulations sample a wide range of mechanosensitive K2P channel structures Changes in the pressure profile and state-dependent lipid interactions play a key role Lipid block of the inner pore does not mediate stretch activation Aryal et al. use MD simulations to understand stretch activation of the mechanosensitive K2P channel, TREK-2. They demonstrate how a change in forces within the bilayer drives movement between different conformations, and investigate the role that lipids play in this process.