Function And Structure Of

The Natural Thyroid Diet

The Natural Thyroid Diet

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NIS couples the inward translocation of down its electrochemical gradient to the simultaneous inward "uphill" translocation of I" against its electrochemical gradient. NIS activity is inhibited by the "classic" competitive inhibitors perchlorate and thio-cyanate (9, 15-18). Two Na+ are transported per each I- (19). The Na+ gradient that provides the driving force for uptake is maintained by the ATPase. In the thyroid, both NIS and the Na+/K+ ATPase are located on the basolateral side of the thyroid follicular cells, facing the blood supply (20). Rat NIS (rNIS) is a 618-amino acid protein (relative molecular mass 65,196) (4); both human and pig NIS, which contain 643 amino acids each, are highly homologous (75.9% and 74.2%, respectively) to rNIS (6, 7). Based on extensive experimental testing, we have proposed a NIS secondary structure model with 13 transmembrane segments (Figure 1) (12). The amino and carboxy termini face extra- and intracellularly, respectively (10). NIS is a glycoprotein; three of its Asp residues (225, 485, 497) are glycosylated in the endoplas-mic reticulum (21). However, glycosylation is not essential for proper NIS function, as indicated by the observation that a non-glycosylated NIS protein is properly targeted to the plasma membrane and displays transport activity with an identical Kmvalue (~20-30 (iM) to that ofwild-type (WT) NIS (21). The ca 70-amino acid hydrophilic carboxy terminus is the main phosphorylated region of the protein (22). Freeze-fracture electron microscopy studies of NIS-expressing Xenopus laevis oocytes revealed the appearance of 9-nm intramembrane particles corresponding to NIS (19). The size of these particles suggested that NIS may function as a multimeric protein. Recent co-immunoprecipitation experiments indicate that NIS is indeed an oligomer (23). A putative leucine zipper motif constituted by leucines at positions 199, 206, 213 and 220 may be the structural basis for NIS oligomerization (4).

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Figure 1. Iodide transport and biosynthetic pathway of thyroid hormones T3 and T4 in the thyroid follicular cell. Thyroid follicles are comprised of a layer of epithelial cells surrounding the colloid. The basolateral surface of the cell is shown on the left side of the figure, and the apical surface on the right. Active accumulation of I-, mediated by the symporter (NIS) [top circle], driven by the

Na+ gradient generated by the Na+/K+ ATPase [bottom circle]; once I- effluxes towards the colloid [cylinder], (TPO) [triangle] catalyzes the organification of I- on the thyroglobulin (Tg) molecule. Dotted line pointing from the apical to the basolateral surface indicates endocytosis of iodinated Tg, followed by its phagolysosomal hydrolysis and secretion of thyroid hormones.

Secondary structure model of NIS. Transmembrane segments are numbered with Roman numerals I-XIII. The N-terminus faces the extracellular milieu and the C-terminus the cytosol. N-glycosylation sites are indicated by arrows and the leucine zipper motif in the VI transmembrane segment is shaded gray. Serines on the C-terminus are indicated.

Figure 1. Iodide transport and biosynthetic pathway of thyroid hormones T3 and T4 in the thyroid follicular cell. Thyroid follicles are comprised of a layer of epithelial cells surrounding the colloid. The basolateral surface of the cell is shown on the left side of the figure, and the apical surface on the right. Active accumulation of I-, mediated by the symporter (NIS) [top circle], driven by the

Na+ gradient generated by the Na+/K+ ATPase [bottom circle]; once I- effluxes towards the colloid [cylinder], (TPO) [triangle] catalyzes the organification of I- on the thyroglobulin (Tg) molecule. Dotted line pointing from the apical to the basolateral surface indicates endocytosis of iodinated Tg, followed by its phagolysosomal hydrolysis and secretion of thyroid hormones.

Secondary structure model of NIS. Transmembrane segments are numbered with Roman numerals I-XIII. The N-terminus faces the extracellular milieu and the C-terminus the cytosol. N-glycosylation sites are indicated by arrows and the leucine zipper motif in the VI transmembrane segment is shaded gray. Serines on the C-terminus are indicated.

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