Piezo1 Forms Specific, Functionally Important Interactions with Phosphoinositides and Cholesterol
Piezo1 Forms Specific, Functionally Important Interactions with Phosphoinositides and Cholesterol
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DOI：
10.1016/j.bpj.2020.07.043
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发表时间：
2020-10-20
影响因子：
3.4
通讯作者：
Corry, Ben
中科院分区：
文献类型：
--
作者：
Buyan, Amanda;Cox, Charles D.;Corry, Ben
触觉、听觉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。一种这样的通道是Piezol，其在人类机械刺激的转导中起关键作用，并且与疾病如干细胞症和淋巴发育不良有关。有证据表明，Piezol可以通过膜环境进行调节，通道的活性由脂质（如胆固醇和磷酸肌醇）的局部浓度决定。为了更好地了解Piezol与其环境的相互作用，我们在含有60多种不同脂质类型的复杂哺乳动物双层中进行了蛋白质的模拟，以及电生理学和诱变实验。我们发现，蛋白质改变其局部膜组成，富集特定的脂质，并形成磷酸肌醇和胆固醇的重要结合位点，这些位点在功能上相关，并且通常与Piezol介导的病理学相关。我们还确定了一些关键的结构连接之间的螺旋桨和孔域位于接近脂质结合位点。
Touch, hearing, and blood pressure regulation require mechanically gated ion channels that convert mechanical stimuli into electrical currents. One such channel is Piezol, 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 Piezol 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 Piezol 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 Piezol -mediated pathologies. We also identify a number of key structural connections between the propeller and pore domains located close to lipid-binding sites.