Iodide Binding in Sodium-Coupled Cotransporters

Abstract

Several apical iodide translocation pathways have been proposed for iodide efflux out of thyroid follicular cells, including a pathway mediated by the sodium-coupled monocarboxylate transporter 1 (SMCT1), which remains controversial. Herein, we evaluate structural and functional similarities between SMCT1 and the well-studied sodium-iodide symporter (NIS) that mediates the first step of iodide entry into the thyroid. Free-energy calculations using a force field with electronic polarizability verify the presence of a conserved iodide-binding pocket between the TM2, TM3, and TM7 segments in hNIS, where iodide is coordinated by Phe67, Gln72, Cys91, and Gln94. We demonstrate the mutation of residue Gly93 of hNIS to a larger amino acid expels the side chain of a critical tryptophan residue (Trp255) into the interior of the binding pocket, partially occluding the iodide binding site and reducing iodide affinity, which is consistent with previous reports associating mutation of this residue with iodide uptake deficiency and hypothyroidism. Furthermore, we find that the position of Trp255 in this hNIS mutant mirrors that of Trp253 in wild-type hSMCT1, where a threonine (Thr91) occupies the position homologous to that occupied by glycine in wild-type hNIS (Gly93). Correspondingly, mutation of Thr91 to glycine in hSMCT1 makes the pocket structure more like that of wild-type hNIS, increasing its iodide affinity. These results suggest that wild-type hSMCT1 in the inward-facing conformation may bind iodide only very weakly, which may have implications for its ability to transport iodide.

Inter-species variation in monovalent anion substrate selectivity and inhibitor sensitivity in the sodium iodide symporter (NIS)

“…Mutation of G93 to T, N, Q, E, or D shifts the stoichiometry of perchlorate transport from electroneutral to electrogenic [52]. However, our group and others hypothesize that G93X mutations disrupt Q94, which we model as part of the ion binding site [53].…”

“…Blue diamonds indicate additional negatively charged residues in minke whale NIS. Bold red lettering indicates residue reported to be involved in stoichiometry control and translocation dynamics [52][53]. Numbering follows human NIS.…”

“…The exact mechanism of this stoichiometric shift is unknown. Mutagenesis and modeling studies indicate that glycine 93 (G93) and glutamic acid 94 (Q94) play a role in controlling substrate stoichiometry and ion coordination in conjunction with tryptophan 255 (W255) and tyrosine 259 (Y259) [52,53]. Mutation of G93 to T, N, Q, E, or D shifts the stoichiometry of perchlorate transport from electroneutral to electrogenic [52].…”

“…No mechanism has been identified to explain the different affinities for these chemically similar anions. Several studies have speculated that anion size plays a role, especially if selectivity and affinity are introduced in the ion binding pocket, where free movement of the ions may be restricted, and size may be an exclusion factor [13][14][15][52][53][54].…”

Amiodarone-induced thyrotoxicosis type 2: predictors and treatment options

“…Таким образом формируются стойкие внутриклеточные депо с очень медленным высвобождением препарата [17]. Кроме того, Ам повреждает мембранные белки-транспортировщики: хлористо-йодный транспортер (пендрин), переносчик йодистого натрия и апикальный йодидный транспортер [25].…”