Department of Chemistry, Texas A&M University, College Station, TX, USA.
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
Nat Chem Biol. 2021 Jan;17(1):89-95. doi: 10.1038/s41589-020-00659-5. Epub 2020 Sep 28.
TRAAK is an ion channel from the two-pore domain potassium (K) channel family with roles in maintaining the resting membrane potential and fast action potential conduction. Regulated by a wide range of physical and chemical stimuli, the affinity and selectivity of K4.1 toward lipids remains poorly understood. Here we show the two isoforms of K4.1 have distinct binding preferences for lipids dependent on acyl chain length and position on the glycerol backbone. The channel can also discriminate the fatty acid linkage at the SN position. Of the 33 lipids interrogated using native mass spectrometry, phosphatidic acid had the lowest equilibrium dissociation constants for both isoforms of K4.1. Liposome potassium flux assays with K4.1 reconstituted in defined lipid environments show that those containing phosphatidic acid activate the channel in a dose-dependent fashion. Our results begin to define the molecular requirements for the specific binding of lipids to K4.1.
TRAAK 是双孔域钾 (K) 通道家族的一种离子通道，在维持静息膜电位和快速动作电位传导中发挥作用。受广泛的物理和化学刺激调节，K4.1 对脂质的亲和力和选择性仍知之甚少。在这里，我们展示了两种 K4.1 同工型对脂质具有不同的结合偏好，这取决于酰基链长度和甘油骨架上的位置。该通道还可以区分 SN 位置上的脂肪酸键合。在使用天然质谱法检测的 33 种脂质中，磷脂酸对两种 K4.1 同工型的平衡解离常数最低。在具有定义脂质环境的 K4.1 重建的脂质体钾通量测定中，含有磷脂酸的脂质体以剂量依赖性方式激活通道。我们的结果开始定义脂质与 K4.1 特异性结合的分子要求。
