From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca2+ binding stimulates its open conformation by altering the structure of transmembrane helices that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl- channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca2+-activated Cl- channel convert it into a robust scramblase.

中文翻译：

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脂质和离子通过 nhTMEM16 加扰酶中的相同物理途径穿过膜

从细菌到哺乳动物，不同的磷脂种类通过 ATP 依赖性脂质转运蛋白在质膜的内叶和外叶之间分离。不依赖 ATP 的磷脂扰乱对这种不对称性的破坏在细胞信号传导中很重要，但其机制仍不完全清楚。使用 MD 模拟与实验分析相结合，我们表明暴露于真菌加扰酶 nhTMEM16 上脂质双层的表面亲水性跨膜腔可作为脂质易位和跨膜离子传导的途径。Ca2+ 结合通过改变排列空腔的跨膜螺旋结构来刺激其开放构象。