Dimerization of the sodium/iodide symporter

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Dimerization of the sodium/iodide symporter. / Thompson, Rebecca J; Fletcher, Alice; Brookes, Katie; Nieto, Hannah; Alshahrani, Mohammed M; Mueller, Jonathan W; Fine, Nicholas H F; Hodson, David J; Boelaert, Kristien; Read, Martin L; Smith, Vicki E; McCabe, Christopher J.

In: Thyroid, Vol. 29, No. 10, 10.2019, p. 1485-1498.

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Thompson RJ, Fletcher A, Brookes K, Nieto H, Alshahrani MM, Mueller JW et al. Dimerization of the sodium/iodide symporter. Thyroid. 2019 Oct;29(10):1485-1498. https://doi.org/10.1089/thy.2019.0034

Author

Thompson, Rebecca J ; Fletcher, Alice ; Brookes, Katie ; Nieto, Hannah ; Alshahrani, Mohammed M ; Mueller, Jonathan W ; Fine, Nicholas H F ; Hodson, David J ; Boelaert, Kristien ; Read, Martin L ; Smith, Vicki E ; McCabe, Christopher J. / Dimerization of the sodium/iodide symporter. In: Thyroid. 2019 ; Vol. 29, No. 10. pp. 1485-1498.

Bibtex

@article{5d8219de66764e0e9ec797e6b7c69a2f,
title = "Dimerization of the sodium/iodide symporter",
abstract = "The ability of thyroid follicular epithelial cells to accumulate iodide via the sodium/iodide symporter (NIS) is exploited to successfully treat most thyroid cancers, although a subset of patients lose functional NIS activity and become unresponsive to radioiodide therapy, with poor clinical outcome. Our knowledge of NIS regulation remains limited, however. While numerous membrane proteins are functionally regulated via dimerization, there is little definitive evidence of NIS dimerization, and whether this might impact upon radioiodide uptake and treatment success is entirely unknown. We hypothesized that NIS dimerizes and that dimerization is a prerequisite for iodide uptake. Methods: Coimmunoprecipitation, proximity ligation, and F{\"o}rster resonance energy transfer (FRET) assays were used to assess NIS:NIS interaction. To identify residues involved in dimerization, a homology model of NIS structure was built based on the crystal structure of the dimeric bacterial protein vSGLT. Results: Abundant cellular NIS dimerization was confirmed in vitro via three discrete methodologies. FRET and proximity ligation assays demonstrated that while NIS can exist as a dimer at the plasma membrane (PM), it is also apparent in other cellular compartments. Homology modeling revealed one key potential site of dimeric interaction, with six residues <3{\AA} apart. In particular, NIS residues Y242, T243, and Q471 were identified as critical to dimerization. Individual mutation of residues Y242 and T243 rendered NIS nonfunctional, while abrogation of Q471 did not impact radioiodide uptake. FRET data show that the putative dimerization interface can tolerate the loss of one, but not two, of these three clustered residues. Conclusions: We show for the first time that NIS dimerizes in vitro, and we identify the key residues via which this happens. We hypothesize that dimerization of NIS is critical to its trafficking to the PM and may therefore represent a new mechanism that would need to be considered in overcoming therapeutic failure in patients with thyroid cancer.",
keywords = "NIS, radioiodide uptake, dimerization, thyroid",
author = "Thompson, {Rebecca J} and Alice Fletcher and Katie Brookes and Hannah Nieto and Alshahrani, {Mohammed M} and Mueller, {Jonathan W} and Fine, {Nicholas H F} and Hodson, {David J} and Kristien Boelaert and Read, {Martin L} and Smith, {Vicki E} and McCabe, {Christopher J}",
year = "2019",
month = "10",
doi = "10.1089/thy.2019.0034",
language = "English",
volume = "29",
pages = "1485--1498",
journal = "Thyroid",
issn = "1050-7256",
publisher = "Mary Ann Liebert",
number = "10",

}

RIS

TY - JOUR

T1 - Dimerization of the sodium/iodide symporter

AU - Thompson, Rebecca J

AU - Fletcher, Alice

AU - Brookes, Katie

AU - Nieto, Hannah

AU - Alshahrani, Mohammed M

AU - Mueller, Jonathan W

AU - Fine, Nicholas H F

AU - Hodson, David J

AU - Boelaert, Kristien

AU - Read, Martin L

AU - Smith, Vicki E

AU - McCabe, Christopher J

PY - 2019/10

Y1 - 2019/10

N2 - The ability of thyroid follicular epithelial cells to accumulate iodide via the sodium/iodide symporter (NIS) is exploited to successfully treat most thyroid cancers, although a subset of patients lose functional NIS activity and become unresponsive to radioiodide therapy, with poor clinical outcome. Our knowledge of NIS regulation remains limited, however. While numerous membrane proteins are functionally regulated via dimerization, there is little definitive evidence of NIS dimerization, and whether this might impact upon radioiodide uptake and treatment success is entirely unknown. We hypothesized that NIS dimerizes and that dimerization is a prerequisite for iodide uptake. Methods: Coimmunoprecipitation, proximity ligation, and Förster resonance energy transfer (FRET) assays were used to assess NIS:NIS interaction. To identify residues involved in dimerization, a homology model of NIS structure was built based on the crystal structure of the dimeric bacterial protein vSGLT. Results: Abundant cellular NIS dimerization was confirmed in vitro via three discrete methodologies. FRET and proximity ligation assays demonstrated that while NIS can exist as a dimer at the plasma membrane (PM), it is also apparent in other cellular compartments. Homology modeling revealed one key potential site of dimeric interaction, with six residues <3Å apart. In particular, NIS residues Y242, T243, and Q471 were identified as critical to dimerization. Individual mutation of residues Y242 and T243 rendered NIS nonfunctional, while abrogation of Q471 did not impact radioiodide uptake. FRET data show that the putative dimerization interface can tolerate the loss of one, but not two, of these three clustered residues. Conclusions: We show for the first time that NIS dimerizes in vitro, and we identify the key residues via which this happens. We hypothesize that dimerization of NIS is critical to its trafficking to the PM and may therefore represent a new mechanism that would need to be considered in overcoming therapeutic failure in patients with thyroid cancer.

AB - The ability of thyroid follicular epithelial cells to accumulate iodide via the sodium/iodide symporter (NIS) is exploited to successfully treat most thyroid cancers, although a subset of patients lose functional NIS activity and become unresponsive to radioiodide therapy, with poor clinical outcome. Our knowledge of NIS regulation remains limited, however. While numerous membrane proteins are functionally regulated via dimerization, there is little definitive evidence of NIS dimerization, and whether this might impact upon radioiodide uptake and treatment success is entirely unknown. We hypothesized that NIS dimerizes and that dimerization is a prerequisite for iodide uptake. Methods: Coimmunoprecipitation, proximity ligation, and Förster resonance energy transfer (FRET) assays were used to assess NIS:NIS interaction. To identify residues involved in dimerization, a homology model of NIS structure was built based on the crystal structure of the dimeric bacterial protein vSGLT. Results: Abundant cellular NIS dimerization was confirmed in vitro via three discrete methodologies. FRET and proximity ligation assays demonstrated that while NIS can exist as a dimer at the plasma membrane (PM), it is also apparent in other cellular compartments. Homology modeling revealed one key potential site of dimeric interaction, with six residues <3Å apart. In particular, NIS residues Y242, T243, and Q471 were identified as critical to dimerization. Individual mutation of residues Y242 and T243 rendered NIS nonfunctional, while abrogation of Q471 did not impact radioiodide uptake. FRET data show that the putative dimerization interface can tolerate the loss of one, but not two, of these three clustered residues. Conclusions: We show for the first time that NIS dimerizes in vitro, and we identify the key residues via which this happens. We hypothesize that dimerization of NIS is critical to its trafficking to the PM and may therefore represent a new mechanism that would need to be considered in overcoming therapeutic failure in patients with thyroid cancer.

KW - NIS

KW - radioiodide uptake

KW - dimerization

KW - thyroid

UR - http://www.scopus.com/inward/record.url?scp=85073490559&partnerID=8YFLogxK

U2 - 10.1089/thy.2019.0034

DO - 10.1089/thy.2019.0034

M3 - Article

C2 - 31310151

VL - 29

SP - 1485

EP - 1498

JO - Thyroid

JF - Thyroid

SN - 1050-7256

IS - 10

ER -