Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism

Author:

Chi Ximin12ORCID,Chen Yiming3ORCID,Li Yaning245ORCID,Dai Lu4,Zhang Yuanyuan2ORCID,Shen Yaping2ORCID,Chen Yun26,Shi Tianhao4ORCID,Yang Haonan4,Wang Zilong3ORCID,Yan Renhong4ORCID

Affiliation:

1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Science, Xiamen University, Xiamen 361102, Fujian Province, China.

2. Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China.

3. Department of Medical Neuroscience, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong Province, China.

4. Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen 518055, Guangdong Province, China.

5. Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.

6. Novoprotein Scientific Inc., Suzhou 215000, China.

Abstract

The solute carrier 13 (SLC13) family comprises electrogenic sodium ion–coupled anion cotransporters, segregating into sodium ion–sulfate cotransporters (NaSs) and sodium ion–di- and–tricarboxylate cotransporters (NaDCs). NaS1 and NaDC1 regulate sulfate homeostasis and oxidative metabolism, respectively. NaS1 deficiency affects murine growth and fertility, while NaDC1 affects urinary citrate and calcium nephrolithiasis. Despite their importance, the mechanisms of substrate recognition and transport remain insufficiently characterized. In this study, we determined the cryo–electron microscopy structures of human NaS1, capturing inward-facing and combined inward-facing/outward-facing conformations within a dimer both in apo and sulfate-bound states. In addition, we elucidated NaDC1’s outward-facing conformation, encompassing apo, citrate-bound, and N -( p -amylcinnamoyl) anthranilic acid (ACA) inhibitor–bound states. Structural scrutiny illuminates a detailed elevator mechanism driving conformational changes. Notably, the ACA inhibitor unexpectedly binds primarily anchored by transmembrane 2 (TM2), Loop 10, TM11, and TM6a proximate to the cytosolic membrane. Our findings provide crucial insights into SLC13 transport mechanisms, paving the way for future drug design.

Publisher

American Association for the Advancement of Science (AAAS)

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