Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, Beijing 100853, China.
Sci Adv. 2024 Nov 22;10(47):eado6778. doi: 10.1126/sciadv.ado6778.
Sulfate (SO) is a pivotal inorganic anion with essential roles in mammalian physiology. NaS1, a member of solute carrier 13 family and divalent anion/sodium symporter family, functions as a Na-sulfate cotransporter, facilitating sulfate (re)absorption across renal proximal tubule and small intestine epithelia. While previous studies have linked several human disorders to mutations in the gene, its transport mechanism remains unclear. Here, we report the cryo-electron microscopy structures of five distinct conformations of the human NaS1 at resolutions of 2.7 to 3.3 angstroms, revealing the substrates recognition mechanism and the conformational change of NaS1 during the Na-sulfate cotransport cycle. Our studies delineate the molecular basis of the detailed dynamic transport cycle of NaS1. These findings advance the current understanding of the Na-sulfate cotransport mechanism, human sulfate (re)absorption, and the implications of disease-associated NaS1 mutations.
硫酸盐（SO）是一种重要的无机阴离子，在哺乳动物生理学中具有重要作用。NaS1 是溶质载体 13 家族和二价阴离子/钠同向转运体家族的成员，作为 Na-硫酸盐共转运体发挥作用，促进肾脏近端小管和小肠上皮细胞中的硫酸盐（再）吸收。虽然先前的研究将几种人类疾病与 基因的突变联系起来，但它的运输机制仍不清楚。在这里，我们报告了人类 NaS1 的五个不同构象的冷冻电子显微镜结构，分辨率为 2.7 到 3.3 埃，揭示了底物识别机制和 NaS1 在 Na-硫酸盐共转运循环中的构象变化。我们的研究描绘了 NaS1 详细的动态转运循环的分子基础。这些发现推进了对 Na-硫酸盐共转运机制、人类硫酸盐（再）吸收以及与疾病相关的 NaS1 突变的影响的现有理解。
