Touch, hearing, and blood pressure regulation require mechanically gated ion channels that convert mechanical stimuli into electrical currents. One such channel is Piezo1, which plays a key role in the transduction of mechanical stimuli in humans and is implicated in diseases, such as xerocytosis and lymphatic dysplasia. There is building evidence that suggests Piezo1 can be regulated by the membrane environment, with the activity of the channel determined by the local concentration of lipids, such as cholesterol and phosphoinositides. To better understand the interaction of Piezo1 with its environment, we conduct simulations of the protein in a complex mammalian bilayer containing more than 60 different lipid types together with electrophysiology and mutagenesis experiments. We find that the protein alters its local membrane composition, enriching specific lipids and forming essential binding sites for phosphoinositides and cholesterol that are functionally relevant and often related to Piezo1-mediated pathologies. We also identify a number of key structural connections between the propeller and pore domains located close to lipid-binding sites.

中文翻译：

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Piezo1 与磷酸肌醇、胆固醇和其他脂质类型形成特定的、功能上重要的相互作用


触觉、听力和血压调节需要机械门控离子通道，将机械刺激转化为电流。 Piezo1 就是这样的通道之一，它在人类机械刺激的转导中发挥着关键作用，并与干细胞增多症和淋巴管发育不良等疾病有关。越来越多的证据表明 Piezo1 可以受到膜环境的调节，通道的活性由胆固醇和磷酸肌醇等脂质的局部浓度决定。为了更好地了解 Piezo1 与其环境的相互作用，我们对包含 60 多种不同脂质类型的复杂哺乳动物双层中的蛋白质进行了模拟，并进行了电生理学和诱变实验。我们发现该蛋白质改变其局部膜组成，富集特定脂质并形成磷酸肌醇和胆固醇的重要结合位点，这些结合位点在功能上相关并且通常与 Piezo1 介导的病理学相关。我们还确定了螺旋桨和靠近脂质结合位点的孔结构域之间的许多关键结构连接。