Allosteric activation of an ion channel triggered by modification of mechanosensitive nano-pockets.,Nature Communications

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Allosteric activation of an ion channel triggered by modification of mechanosensitive nano-pockets.
Nature Communications ( IF 14.7 ) Pub Date : 2019-10-10 , DOI: 10.1038/s41467-019-12591-x
Charalampos Kapsalis ₁ , Bolin Wang _{1,

2,

3} , Hassane El Mkami _{4,

5} , Samantha J Pitt ₆ , Jason R Schnell ₇ , Terry K Smith ₈ , Jonathan D Lippiat ₃ , Bela E Bode _{5,

8} , Christos Pliotas _{1,

2,

3,

5}

Affiliation

Lipid availability within transmembrane nano-pockets of ion channels is linked with mechanosensation. However, the effect of hindering lipid-chain penetration into nano-pockets on channel structure has not been demonstrated. Here we identify nano-pockets on the large conductance mechanosensitive channel MscL, the high-pressure threshold channel. We restrict lipid-chain access to the nano-pockets by mutagenesis and sulfhydryl modification, and monitor channel conformation by PELDOR/DEER spectroscopy. For a single site located at the entrance of the nano-pockets and distal to the channel pore we generate an allosteric response in the absence of tension. Single-channel recordings reveal a significant decrease in the pressure activation threshold of the modified channel and a sub-conducting state in the absence of applied tension. Threshold is restored to wild-type levels upon reduction of the sulfhydryl modification. The modification associated with the conformational change restricts lipid access to the nano-pocket, interrupting the contact between the membrane and the channel that mediates mechanosensitivity.

中文翻译：

由机械敏感纳米口袋的修饰触发的离子通道的变构激活。

离子通道的跨膜纳米袋内的脂质可用性与机械感觉有关。然而，阻碍脂质链渗透到纳米口袋中对通道结构的影响尚未得到证实。在这里，我们确定了大电导机械敏感通道 MscL（高压阈值通道）上的纳米口袋。我们通过诱变和巯基修饰限制脂质链进入纳米口袋，并通过 PELDOR/DEER 光谱监测通道构象。对于位于纳米口袋入口处且远离通道孔的单个位点，我们在没有张力的情况下产生变构反应。单通道记录显示修改通道的压力激活阈值显着降低，并且在没有施加张力的情况下处于亚导电状态。巯基修饰减少后，阈值恢复到野生型水平。与构象变化相关的修饰限制了脂质进入纳米袋，中断了膜与介导机械敏感性的通道之间的接触。

更新日期：2019-10-10

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