Structural insights into the gating mechanism of human SLC26A9 mediated by its C-terminal sequence
Structural insights into the gating mechanism of human SLC26A9 mediated by its C-terminal sequence
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对人 SLC26A9 C 端序列介导的门控机制的结构见解
DOI：
10.1038/s41421-020-00193-7
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发表时间：
2020-08-10
期刊：
影响因子：
33.5
通讯作者：
Pan, Xiaojing
中科院分区：
文献类型：
--
作者：
Chi, Ximin;Jin, Xueqin;Pan, Xiaojing
人类SLC26转运蛋白家族表现出多种转运特性，家族成员SLC26A9发挥多种作用，包括充当Cl-/HCO(3)(-)交换器、Cl(-)通道和Na(+)转运蛋白。 SLC26A9 的一些突变与呼吸和消化系统的异常相关。作为囊性纤维化患者中与 CFTR 共定位的潜在靶点，SLC26A9 在药物开发中具有重要价值。在这里，我们展示了人类 SLC26A9 二聚体的冷冻电镜结构，分辨率为 2.6 埃。 C末端的一段与假定的转运途径的细胞内前庭的入口结合，该途径已被电生理学实验证明是门控调节剂。多个氯离子和钠离子在高分辨率结构中得到解析，首次识别出新型离子结合袋。总之，我们的结构在阐明 SLC26A9 的结构特征和调控机制方面迈出了重要一步，在囊性纤维化的治疗中具有潜在意义。
The human SLC26 transporter family exhibits various transport characteristics, and family member SLC26A9 performs multiple roles, including acting as Cl-/HCO(3)(-)exchangers, Cl(-)channels, and Na(+)transporters. Some mutations of SLC26A9 are correlated with abnormalities in respiration and digestion systems. As a potential target colocalizing with CFTR in cystic fibrosis patients, SLC26A9 is of great value in drug development. Here, we present a cryo-EM structure of the human SLC26A9 dimer at 2.6 angstrom resolution. A segment at the C-terminal end is bound to the entry of the intracellular vestibule of the putative transport pathway, which has been proven by electrophysiological experiments to be a gating modulator. Multiple chloride and sodium ions are resolved in the high-resolution structure, identifying novel ion-binding pockets for the first time. Together, our structure takes important steps in elucidating the structural features and regulatory mechanism of SLC26A9, with potential significance in the treatment of cystic fibrosis.