Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich, Jülich, Germany.
Institute of Clinical Pharmacology, RWTH Aachen University, Aachen, Germany.
Nat Commun. 2021 May 14;12(1):2826. doi: 10.1038/s41467-021-22724-w.
TMEM16 lipid scramblases transport lipids and also operate as ion channels with highly variable ion selectivities and various physiological functions. However, their molecular mechanisms of ion conduction and selectivity remain largely unknown. Using computational electrophysiology simulations at atomistic resolution, we identified the main ion-conductive state of TMEM16 lipid scramblases, in which an ion permeation pathway is lined by lipid headgroups that directly interact with permeating ions in a voltage polarity-dependent manner. We found that lipid headgroups modulate the ion-permeability state and regulate ion selectivity to varying degrees in different scramblase isoforms, depending on the amino-acid composition of the pores. Our work has defined the structural basis of ion conduction and selectivity in TMEM16 lipid scramblases and uncovered the mechanisms responsible for the direct effects of membrane lipids on the conduction properties of ion channels.
TMEM16 脂质翻转酶既能转运脂类，又能作为离子通道发挥作用，其离子选择性具有高度可变性，并具有多种生理功能。然而，其离子传导和选择性的分子机制在很大程度上仍不清楚。本研究采用原子分辨率的计算电生理学模拟，确定了 TMEM16 脂质翻转酶的主要离子传导状态，在此状态下，离子渗透途径由与渗透离子直接相互作用的脂头部基团排列而成，这种相互作用具有电压极性依赖性。研究发现，脂头部基团在不同的翻转酶异构体中以不同的程度调节离子通透性状态和离子选择性，这取决于孔道的氨基酸组成。本工作定义了 TMEM16 脂质翻转酶中离子传导和选择性的结构基础，并揭示了膜脂对离子通道传导特性的直接影响的作用机制。
