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.

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分离在质膜的内叶和外叶之间。通过不依赖ATP的磷脂扰乱破坏这种不对称性在细胞信号转导中很重要，但其机理尚不完全清楚。使用MD模拟与实验分析相结合，我们表明暴露于真菌scramblase nhTMEM16上的脂质双层的表面亲水性跨膜腔可作为脂质转运和跨膜离子传导的途径。钙²⁺结合通过改变排列在腔中的跨膜螺旋的结构来刺激其开放构象。我们已经确定密钥氨基磷脂加扰酸必要和验证的想法，离子渗透TMEM16氯^-通过显示在TMEM16A Ca的孔径区域中的两个残基的那突变经由结构上同源的通路通道²⁺ -活化氯^-信道将其转换变成健壮的乱码酶。