Structural insights into brain thyroid hormone transport via MCT8 and OATP1C1

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Thyroid hormones are essential for neurological development.
• The solute carrier (SLC) transporters MCT8 and OATP1C1 facilitate thyroid hormone transport across the blood-brain barrier.
• Mutations in MCT8 cause Allan-Herndon-Dudley syndrome (AHDS), while OATP1C1 deficiency is linked to neurodegeneration.

Purpose of the Study:

• To determine the structures of MCT8 and OATP1C1 bound to thyroid hormones.
• To elucidate the distinct mechanisms of thyroid hormone recognition and transport by MCT8 and OATP1C1.
• To explain the molecular basis of disease-associated mutations.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to obtain high-resolution structures.
• Functional studies to analyze transporter activity.
• Structural analysis to understand hormone binding and transport.

Main Results:

• Determined cryo-EM structures of MCT8 and OATP1C1 with triiodothyronine (T3) and thyroxine (T4) at 2.9 and 2.3 Å resolution, respectively.
• Elucidated distinct mechanisms for thyroid hormone recognition and transport by the two transporters.
• Identified an extracellular allosteric site in OATP1C1, a novel feature for SLC transporters.
• Provided structural explanations for disease-causing mutations.

Conclusions:

• The study reveals the molecular mechanisms underlying thyroid hormone transport by MCT8 and OATP1C1.
• Structural insights explain the pathophysiology of AHDS and OATP1C1 deficiency-related neurological disorders.
• Findings advance our understanding of thyroid hormone homeostasis and its role in development and disease.