Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USA.
Nat Commun. 2022 Nov 17;13(1):7017. doi: 10.1038/s41467-022-34813-5.
Pentameric ligand-gated ion channels (pLGICs) mediate synaptic transmission and are sensitive to their lipid environment. The mechanism of phospholipid modulation of any pLGIC is not well understood. We demonstrate that the model pLGIC, ELIC (Erwinia ligand-gated ion channel), is positively modulated by the anionic phospholipid, phosphatidylglycerol, from the outer leaflet of the membrane. To explore the mechanism of phosphatidylglycerol modulation, we determine a structure of ELIC in an open-channel conformation. The structure shows a bound phospholipid in an outer leaflet site, and structural changes in the phospholipid binding site unique to the open-channel. In combination with streamlined alchemical free energy perturbation calculations and functional measurements in asymmetric liposomes, the data support a mechanism by which an anionic phospholipid stabilizes the activated, open-channel state of a pLGIC by specific, state-dependent binding to this site.
五聚体配体门控离子通道（pLGICs）介导突触传递，并对其脂质环境敏感。然而，任何 pLGIC 的磷脂调节机制都还没有被很好地理解。我们证明，模式 pLGIC，即 ELIC（Erwinia 配体门控离子通道），受到来自膜外叶的阴离子磷脂，即磷脂酰甘油的正向调节。为了探究磷脂酰甘油调节的机制，我们确定了 ELIC 在开放通道构象下的结构。该结构显示了一个结合在外侧叶位的磷脂，以及在开放通道中特有的磷脂结合位点的结构变化。结合流线型的变分自由能计算和不对称脂质体中的功能测量，这些数据支持了一种机制，即阴离子磷脂通过与该位点的特异性、状态依赖的结合，稳定 pLGIC 的激活、开放通道状态。
