Mechanosensitive channels sense mechanical forces in cell membranes and underlie many biological sensing processes^1,2,3. However, how exactly they sense mechanical force remains under investigation⁴. The bacterial mechanosensitive channel of small conductance, MscS, is one of the most extensively studied mechanosensitive channels^4,5,6,7,8, but how it is regulated by membrane tension remains unclear, even though the structures are known for its open and closed states^9,10,11. Here we used cryo-electron microscopy to determine the structure of MscS in different membrane environments, including one that mimics a membrane under tension. We present the structures of MscS in the subconducting and desensitized states, and demonstrate that the conformation of MscS in a lipid bilayer in the open state is dynamic. Several associated lipids have distinct roles in MscS mechanosensation. Pore lipids are necessary to prevent ion conduction in the closed state. Gatekeeper lipids stabilize the closed conformation and dissociate with membrane tension, allowing the channel to open. Pocket lipids in a solvent-exposed pocket between subunits are pulled out under sustained tension, allowing the channel to transition to the subconducting state and then to the desensitized state. Our results provide a mechanistic underpinning and expand on the ‘force-from-lipids’ model for MscS mechanosensation^4,11.

机械敏感通道感知细胞膜中的机械力，是许多生物传感过程^1,2,3的基础。然而，他们究竟如何感知机械力仍有待研究⁴。小电导的细菌机械敏感通道，MscS，是研究最广泛的机械敏感通道之一^4,5,6,7,8，但它如何受膜张力调节仍不清楚，尽管这些结构以其开放和关闭状态^9,10,11. 在这里，我们使用低温电子显微镜来确定 MscS 在不同膜环境中的结构，包括在张力下模拟膜的环境。我们展示了 MscS 在超导和脱敏状态下的结构，并证明 MscS 在开放状态下脂质双层中的构象是动态的。几种相关的脂质在 MscS 机械感觉中具有不同的作用。孔隙脂质是防止关闭状态下的离子传导所必需的。看门人脂质稳定封闭的构象并随着膜张力解离，从而使通道打开。亚基之间暴露于溶剂的口袋中的口袋脂质在持续的张力下被拉出，使通道转变为亚导电状态，然后转变为脱敏状态。^4,11。