Tassinari Matteo, Tanzi Giorgia, Maggiore Francesco, Groeneweg Stefan, van Geest Ferdy S, Freund Matthijs E T, Stavast Christiaan J, Boniardi Irene, Pasqualato Sebastiano, Visser W Edward, Coscia Francesca
Human Technopole, Milano, Italy.
Department of Internal Medicine, Academic Centre for Thyroid Diseases, Erasmus Medical Centre, Rotterdam, The Netherlands.
Nat Commun. 2025 May 14;16(1):4493. doi: 10.1038/s41467-025-59751-w.
Thyroid hormones (the common name for prohormone thyroxine and the bioactive form triiodothyronine) control major developmental and metabolic processes. Release of thyroid hormones from the thyroid gland into the bloodstream and their transport into target cells is facilitated by plasma membrane transporters, including monocarboxylate transporter (MCT)8 and the highly homologous MCT10. However, the molecular mechanism underlying thyroid hormone transport is unknown. The relevance of such transporters is illustrated in patients with MCT8 deficiency, a severe neurodevelopmental and metabolic disorder. Using cryogenic-sample electron microscopy (cryo-EM), we determined the ligand-free and thyroxine-bound human MCT8 structures in the outward-facing state and the thyroxine-bound human MCT10 in the inward-facing state. Our structural analysis revealed a network of conserved gate residues involved in conformational changes upon thyroxine binding, triggering ligand release in the opposite compartment. We then determined the structure of a folded but inactive patient-derived MCT8 mutant, indicating a subtle conformational change which explains its reduced transport activity. Finally, we report a structure of MCT8 bound to its inhibitor silychristin, locked in the outward-facing state, revealing the molecular basis of its action and specificity. Taken together, this study advances mechanistic understanding of normal and disordered thyroid hormone transport.
甲状腺激素（前激素甲状腺素和生物活性形式三碘甲状腺原氨酸的统称）控制着主要的发育和代谢过程。甲状腺激素从甲状腺释放到血液中，并通过质膜转运蛋白（包括单羧酸转运蛋白（MCT）8和高度同源的MCT10）转运到靶细胞中。然而，甲状腺激素转运的分子机制尚不清楚。MCT8缺乏症患者（一种严重的神经发育和代谢障碍）说明了此类转运蛋白的相关性。利用低温样品电子显微镜（cryo-EM），我们确定了处于外向状态的无配体和甲状腺素结合的人MCT8结构以及处于内向状态的甲状腺素结合的人MCT10结构。我们的结构分析揭示了一个保守门控残基网络，这些残基参与甲状腺素结合时的构象变化，从而触发配体在相对隔室中的释放。然后，我们确定了一个折叠但无活性的患者来源的MCT8突变体的结构，表明了一种细微的构象变化，这解释了其转运活性降低的原因。最后，我们报告了与抑制剂水飞蓟宾结合的MCT8结构，其锁定在外向状态，揭示了其作用和特异性的分子基础。综上所述，这项研究推进了对正常和紊乱甲状腺激素转运的机制理解。
