ESPEYB25 3. Thyroid Mechanism of the Year (1 abstracts)
3.1. Molecular mechanism of thyroxine transport by monocarboxylate transporters
Tassinari M , Tanzi G , Maggiore F , Groeneweg S , van Geest FS , Freund MET , Stavast CJ , Boniardi I , Pasqualato S , Visser WE & Coscia F
Nat Commun. 2025 May 14;16(1):4493.doi: 10.1038/s41467-025-59751-w. PMID: 40368961
Brief Summary: Using cryo-electron microscopy, this basic/translational experimental study determined structures of monocarboxylate transporter 8 (MCT8) and MCT10 in multiple transport states: ligand-free MCT8, T4-bound MCT8, silychristin-bound MCT8, a pathogenic MCT8-D424N mutant, and T4-bound MCT10. The study identified critical (single amino acid) residues: R371 (electrostatic coordination), N119 and D424 (gate closure and conformational coupling), that are essential for thyroxine binding and translocation. Silychristin inhibits MCT8 by locking it in an outward-facing state. These findings clarify the molecular mechanism of thyroid hormone transport and explain transport failure in MCT8 deficiency despite preserved T4 binding.
This study provides the first high-resolution structural insight into how thyroid hormones are transported by MCT8 and MCT10, which is critical for understanding intracellular thyroid hormone availability. By identifying specific residues essential for transport—and showing how a pathogenic, disease-causing MCT8 variant disrupts this process, the study elucidates the molecular basis of MCT8 deficiency. Furthermore, it reveals how the flavonolignan silychristin inhibits MCT8, offering a structural framework for future drug design targeting thyroid hormone transporter disorders.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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