Freitas Makayla M, Gouaux Eric
Vollum Institute, Oregon Health and Science University, 3232 SW Research Drive, Portland, OR, USA.
Howard Hughes Medical Institute, Oregon Health and Science University, 3232 SW Research Drive, Portland, OR, USA.
Nat Commun. 2025 Jul 22;16(1):6746. doi: 10.1038/s41467-025-62038-9.
The bile acid-sensitive ion channel (BASIC) is the least understood member of the mammalian epithelial Na channel/degenerin (ENaC/DEG) superfamily of ion channels, which are involved in a variety of physiological processes. While some members of this superfamily, including BASIC, are inhibited by extracellular Ca (Ca), the molecular mechanism underlying Ca modulation remains unclear. Here, by determining the structure of human BASIC (hBASIC) in the presence and absence of Ca using single-particle cryo-electron microscopy (cryo-EM), we reveal Ca-dependent conformational changes in the transmembrane domain and β-linkers. Electrophysiological experiments further show that a glutamate residue in the extracellular vestibule of the pore underpins the Ca-binding site, whose occupancy determines the conformation of the pore and therefore ion flow through the channel. These results reveal the molecular principles governing gating of BASIC and its regulation by Ca ions, demonstrating that Ca ions modulate BASIC function via changes in protein conformation rather than solely from a pore-block, as proposed for other members of this superfamily.
胆汁酸敏感离子通道（BASIC）是哺乳动物上皮钠通道/退化素（ENaC/DEG）离子通道超家族中了解最少的成员，该超家族参与多种生理过程。虽然这个超家族的一些成员，包括BASIC，会受到细胞外钙（Ca）的抑制，但钙调节的分子机制仍不清楚。在这里，通过使用单颗粒冷冻电子显微镜（cryo-EM）确定存在和不存在钙时人BASIC（hBASIC）的结构，我们揭示了跨膜结构域和β连接子中依赖于钙的构象变化。电生理实验进一步表明，孔的细胞外前庭中的一个谷氨酸残基是钙结合位点的基础，其占据情况决定了孔的构象，从而决定了离子通过通道的流动。这些结果揭示了控制BASIC门控及其受钙离子调节的分子原理，表明钙离子通过蛋白质构象的变化而非像该超家族其他成员所提出的仅通过孔阻塞来调节BASIC功能。
