Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Elife. 2019 Jul 24;8:e46986. doi: 10.7554/eLife.46986.
The epithelial anion transporter SLC26A9 contributes to airway surface hydration and gastric acid production. Colocalizing with CFTR, SLC26A9 has been proposed as a target for the treatment of cystic fibrosis. To provide molecular details of its transport mechanism, we present cryo-EM structures and a functional characterization of murine Slc26a9. These structures define the general architecture of eukaryotic SLC26 family members and reveal an unusual mode of oligomerization which relies predominantly on the cytosolic STAS domain. Our data illustrates conformational transitions of Slc26a9, supporting a rapid alternate-access mechanism which mediates uncoupled chloride transport with negligible bicarbonate or sulfate permeability. The characterization of structure-guided mutants illuminates the properties of the ion transport path, including a selective anion binding site located in the center of a mobile module within the transmembrane domain. This study thus provides a structural foundation for the understanding of the entire SLC26 family and potentially facilitates their therapeutic exploitation.
上皮阴离子转运体 SLC26A9 有助于气道表面的水合作用和胃酸分泌。与 CFTR 共定位，SLC26A9 被提议作为囊性纤维化治疗的靶点。为了提供其转运机制的分子细节，我们展示了冷冻电镜结构和对小鼠 Slc26a9 的功能表征。这些结构定义了真核 SLC26 家族成员的一般结构，并揭示了一种不寻常的寡聚化模式，主要依赖于胞质 STAS 结构域。我们的数据说明了 Slc26a9 的构象转变，支持快速交替访问机制，介导不耦合的氯离子转运，几乎没有碳酸氢根或硫酸盐通透性。结构引导突变体的表征阐明了离子运输途径的特性，包括位于跨膜域内可移动模块中心的选择性阴离子结合位点。因此，这项研究为理解整个 SLC26 家族提供了结构基础，并可能促进其治疗应用。
