Du Bowen, Cheng Lili, Xie Jiaying, Chen Ligong, Yan Kaige
Shenzhen Key Laboratory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, 102218, China.
Nat Commun. 2025 Aug 11;16(1):7394. doi: 10.1038/s41467-025-62857-w.
The taurine transporter, TauT, regulates various taurine-mediated physiological and pathological functions by facilitating taurine uptake in a sodium- and chloride-dependent manner. Dysfunction of TauT is associated with male infertility, retinal health and cancers. Despite extensive research efforts, the intricate structure of TauT, the molecular mechanisms underlying taurine transport, and the inhibition mechanisms involved, all remain elusive. Here, we present eleven cryo-electron microscopy (cryo-EM) structures of TauT. The structures TauT bound to substrate (taurine) and substrate analogues (β-alanine, guanidinoacetate, and γ-aminobutyric acid), are captured in distinct conformations. Combining with biochemical analyses, these structures reveal that amino acids Leu134 and Glu406 play a crucial role in substrate specificity within the GABA subfamily. Five distinct inhibitors, namely, piperidine-4-sulfonic acid, imidazole-4-acetatic acid, 5-aminovaleric acid, nipecotic acid and homotaurine, stabilize TauT in an inward-open conformation. Conversely, guanidinoethyl sulphonate stabilizes TauT in the occluded state. These structural insights offer a comprehensive understanding of how these inhibitors counteract taurine transport. Collectively, these findings advance our understanding of the substrate coordination and inhibitor recognition mechanisms of TauT.
牛磺酸转运体（TauT）通过以钠和氯依赖的方式促进牛磺酸摄取，调节各种由牛磺酸介导的生理和病理功能。TauT功能障碍与男性不育、视网膜健康和癌症有关。尽管进行了广泛的研究，但TauT的复杂结构、牛磺酸转运的分子机制以及所涉及的抑制机制仍然不清楚。在此，我们展示了TauT的11个冷冻电镜（cryo-EM）结构。与底物（牛磺酸）和底物类似物（β-丙氨酸、胍基乙酸和γ-氨基丁酸）结合的TauT结构以不同的构象被捕获。结合生化分析，这些结构揭示了亮氨酸134和谷氨酸406在GABA亚家族内的底物特异性中起关键作用。五种不同的抑制剂，即哌啶-4-磺酸、咪唑-4-乙酸、5-氨基戊酸、哌啶酸和高牛磺酸，使TauT稳定在内向开放构象。相反，胍基乙磺酸盐使TauT稳定在封闭状态。这些结构见解提供了对这些抑制剂如何对抗牛磺酸转运的全面理解。总体而言，这些发现推进了我们对TauT底物配位和抑制剂识别机制的理解。
