Molecular mechanism of thyroxine transport by monocarboxylate transporters

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Abstract
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, of which monocarboxylate transporter (MCT)8 and the highly homologous MCT10 are most important. Patients with MCT8 mutations suffer from a severe neurodevelopmental and metabolic disorder, however, the molecular mechanism underlying thyroid hormone transport is unknown. Using cryogenic-sample electron microscopy (cryo-EM), we determined the ligand-free and thyroxine-bound human MCT8 structures in the outward-open 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 on 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. In addition, we determined the structure of MCT8 bound to its inhibitor silychristin, revealing an interaction with residues essential to drive transition to the inward-facing state, thereby locking the protein in the outward-facing state. This study provides molecular and structural insights into normal and disordered thyroid hormone transport.
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