Molecular basis of human taurine transporter uptake and inhibition
Abstract 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 resear...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62857-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849343204732698624 |
|---|---|
| author | Bowen Du Lili Cheng Jiaying Xie Ligong Chen Kaige Yan |
| author_facet | Bowen Du Lili Cheng Jiaying Xie Ligong Chen Kaige Yan |
| author_sort | Bowen Du |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-f787e6cf8a85418a93497035d7e90a01 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f787e6cf8a85418a93497035d7e90a012025-08-20T03:43:09ZengNature PortfolioNature Communications2041-17232025-08-0116111210.1038/s41467-025-62857-wMolecular basis of human taurine transporter uptake and inhibitionBowen Du0Lili Cheng1Jiaying Xie2Ligong Chen3Kaige Yan4Shenzhen Key Laboratory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and TechnologyHepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua UniversityShenzhen Key Laboratory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and TechnologyState Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua UniversityShenzhen Key Laboratory of Biomolecular Assembling and Regulation, School of Life Sciences, Southern University of Science and TechnologyAbstract 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.https://doi.org/10.1038/s41467-025-62857-w |
| spellingShingle | Bowen Du Lili Cheng Jiaying Xie Ligong Chen Kaige Yan Molecular basis of human taurine transporter uptake and inhibition Nature Communications |
| title | Molecular basis of human taurine transporter uptake and inhibition |
| title_full | Molecular basis of human taurine transporter uptake and inhibition |
| title_fullStr | Molecular basis of human taurine transporter uptake and inhibition |
| title_full_unstemmed | Molecular basis of human taurine transporter uptake and inhibition |
| title_short | Molecular basis of human taurine transporter uptake and inhibition |
| title_sort | molecular basis of human taurine transporter uptake and inhibition |
| url | https://doi.org/10.1038/s41467-025-62857-w |
| work_keys_str_mv | AT bowendu molecularbasisofhumantaurinetransporteruptakeandinhibition AT lilicheng molecularbasisofhumantaurinetransporteruptakeandinhibition AT jiayingxie molecularbasisofhumantaurinetransporteruptakeandinhibition AT ligongchen molecularbasisofhumantaurinetransporteruptakeandinhibition AT kaigeyan molecularbasisofhumantaurinetransporteruptakeandinhibition |