Chi Ximin, Jin Xueqin, Chen Yun, Lu Xiaoli, Tu Xinyu, Li Xiaorong, Zhang Yuanyuan, Lei Jianlin, Huang Jing, Huang Zhuo, Zhou Qiang, Pan Xiaojing
Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, Zhejiang 310024 China.
State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084 China.
Cell Discov. 2020 Aug 10;6:55. doi: 10.1038/s41421-020-00193-7. eCollection 2020.
The human SLC26 transporter family exhibits various transport characteristics, and family member SLC26A9 performs multiple roles, including acting as Cl/HCO 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 Å 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.
人类SLC26转运蛋白家族具有多种转运特性，其家族成员SLC26A9发挥多种作用，包括作为Cl⁻/HCO₃⁻交换体、Cl⁻通道和Na⁺转运体。SLC26A9的一些突变与呼吸和消化系统异常相关。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。在此，我们展示了分辨率为2.6 Å的人类SLC26A9二聚体的冷冻电镜结构。C末端的一个片段与假定转运途径的细胞内前庭入口结合，电生理实验已证明该片段是一种门控调节剂。在高分辨率结构中解析出多个氯离子和钠离子，首次确定了新的离子结合口袋。总之，我们的结构在阐明SLC26A9的结构特征和调节机制方面迈出了重要一步，对囊性纤维化的治疗具有潜在意义。
