Histidine residue at position 226 is critical for iodide uptake activity of human sodium/iodide symporter

Wu, Shih-Lu; Ho, Tin Yun; Liang, Ji An; Hsiang, Chien Yun

doi:10.1677/joe-08-0249

Cited by 6 publications

(7 citation statements)

References 25 publications

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“…ITD is an autosomal recessive condition characterized by hypothyroidism, goiter, reduced or absent thyroid uptake of radioiodide, and a low saliva/plasma iodide ratio (1,36). Currently, at least 12 ITD-causing mutations of NIS have been identified (37). Six of these mutations, namely 226delH, T354P, G395R, Q267E, G543E, and V59E have been characterized more thoroughly (38 -41).…”

Section: Congenital Iodide Transport Defect (Itd)mentioning

confidence: 99%

The Sodium-Iodide Symporter NIS and Pendrin in Iodide Homeostasis of the Thyroid

2009

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Thyroid hormones are essential for normal development and metabolism. Thyroid hormone biosynthesis requires iodide uptake into the thyrocytes and efflux into the follicular lumen, where it is organified on selected tyrosyls of thyroglobulin. Uptake of iodide into the thyrocytes is mediated by an intrinsic membrane glycoprotein, the sodium-iodide symporter (NIS), which actively cotransports two sodium cations per each iodide anion. NIS-mediated transport of iodide is driven by the electrochemical sodium gradient generated by the Na(+)/K(+)-ATPase. NIS is expressed in the thyroid, the salivary glands, gastric mucosa, and the lactating mammary gland. TSH and iodide regulate iodide accumulation by modulating NIS activity via transcriptional and posttranscriptional mechanisms. Biallelic mutations in the NIS gene lead to a congenital iodide transport defect, an autosomal recessive condition characterized by hypothyroidism, goiter, low thyroid iodide uptake, and a low saliva/plasma iodide ratio. Pendrin is an anion transporter that is predominantly expressed in the inner ear, the thyroid, and the kidney. Biallelic mutations in the SLC26A4 gene lead to Pendred syndrome, an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. In thyroid follicular cells, pendrin is expressed at the apical membrane. Functional in vitro data and the impaired iodide organification observed in patients with Pendred syndrome support a role of pendrin as an apical iodide transporter.

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Section: Congenital Iodide Transport Defect (Itd)mentioning

confidence: 99%

The Sodium-Iodide Symporter NIS and Pendrin in Iodide Homeostasis of the Thyroid

2009

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“…With regard to iodide transport, experiments yielding a set of residues for which mutation leads to severe defects in NIS-mediated iodide uptake—namely, mutations situated in the transmembrane or intracellular segments— 3 , 75 include the following: (1) mutants of the phosphorylated amino acid residue S43, T49, S227, T577, and S581, 76 (2) kinetic analysis of the extracellular charged H226 residue, 77 (3) deletions in the region spanning residues 234 to 280 of the TM7 segment, 78 (4) mutations of conserved charged amino acids in the extracellular region, 79 and (5) site-directed mutagenesis of the G93, W255, and Y259 residues 21 suggested by a G93R/T354P spontaneous mutation expressed in a patient with a diffuse goiter. 20 Based on the studies of Paroder-Belenitsky et al, 21 we identified a putative iodide-binding pocket comprising transmembrane segments TM2, TM3, and TM7 in hNIS.…”

Section: Discussionmentioning

confidence: 99%

Iodide Binding in Sodium-Coupled Cotransporters

Vergara-Jaque

Fong

Comer

2017

J. Chem. Inf. Model.

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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.

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“…Human NIS cDNA was cloned as described previously [11]. Briefly, two overlapping cDNA fragments representing either the 5'-half or the 3'-half of the complete NIS coding region were amplified and inserted into pBluescript ® II KS (-) vector to create pBKS-NIS-5' and pBKS-NIS-3' plasmids, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction and RT were performed as described previously [11]. RNA integrity was electrophoretically verified by both the ethidium bromide staining and the absorption ratio (OD260/OD280 > 1.95).…”

Section: Methodsmentioning

confidence: 99%

“…Phosphorylation sites (Ser-43, Thr-49, Ser-227, Thr-577, and Ser-581) of NIS have been identified to be important for NIS protein stability and function [10]. In addition, His-226 located in the extracellular region of NIS is critical for iodide transport in our previous study [11]. Moreover, deletion in the region spanning residues 233-280 of NIS loses the iodide uptake activity [12].…”

Section: Introductionmentioning

confidence: 99%

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Conserved charged amino acid residues in the extracellular region of sodium/iodide symporter are critical for iodide transport activity

Kao

et al. 2010

J Biomed Sci

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Background: Sodium/iodide symporter (NIS) mediates the active transport and accumulation of iodide from the blood into the thyroid gland. His-226 located in the extracellular region of NIS has been demonstrated to be critical for iodide transport in our previous study. The conserved charged amino acid residues in the extracellular region of NIS were therefore characterized in this study. Methods: Fourteen charged residues (Arg-9, Glu-79, Arg-82, Lys-86, Asp-163, His-226, Arg-228, Asp-233, Asp-237, Arg-239, Arg-241, Asp-311, Asp-322, and Asp-331) were replaced by alanine. Iodide uptake abilities of mutants were evaluated by steady-state and kinetic analysis. The three-dimensional comparative protein structure of NIS was further modeled using sodium/glucose transporter as the reference protein.

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Histidine residue at position 226 is critical for iodide uptake activity of human sodium/iodide symporter

Cited by 6 publications

References 25 publications

The Sodium-Iodide Symporter NIS and Pendrin in Iodide Homeostasis of the Thyroid

The Sodium-Iodide Symporter NIS and Pendrin in Iodide Homeostasis of the Thyroid

Iodide Binding in Sodium-Coupled Cotransporters

Conserved charged amino acid residues in the extracellular region of sodium/iodide symporter are critical for iodide transport activity

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