Iodide Binding in Sodium-Coupled Cotransporters

Area of Science:

• Molecular biology
• Biophysics
• Cellular physiology

Background:

• Apical iodide efflux from thyroid follicular cells involves proposed pathways, including the controversial sodium-coupled monocarboxylate transporter 1 (SMCT1).
• The sodium-iodide symporter (NIS) mediates the initial iodide uptake into thyroid cells and is well-characterized.

Purpose of the Study:

• To evaluate structural and functional similarities between SMCT1 and NIS.
• To investigate the role of specific residues in iodide binding and transport.

Main Methods:

• Free-energy calculations using a force field with electronic polarizability.
• Site-directed mutagenesis of human NIS (hNIS) and human SMCT1 (hSMCT1) residues.
• Assessment of iodide binding affinity and transport function.

Main Results:

• A conserved iodide-binding pocket was identified in hNIS, involving TM2, TM3, and TM7 segments and coordinating residues Phe67, Gln72, Cys91, and Gln94.
• Mutation of Gly93 in hNIS to a larger amino acid altered the binding pocket and reduced iodide affinity, consistent with hypothyroidism.
• The position of Trp255 in the hNIS mutant mirrored Trp253 in wild-type hSMCT1, and mutating Thr91 to Gly in hSMCT1 increased its iodide affinity, making its pocket resemble wild-type hNIS.

Conclusions:

• Structural similarities exist between the iodide-binding sites of NIS and SMCT1.
• Specific amino acid residues play critical roles in determining iodide affinity and transporter function.
• Wild-type hSMCT1 may exhibit weak iodide binding in its inward-facing conformation, impacting its transport capabilities.