Mechanism of anion selectivity and stoichiometry of the Na +/I - symporter (NIS)

Monika Paroder-Belenitsky, Matthew J. Maestas, Orsolya Dohán, Juan Pablo Nicola, Andrea Reyna-Neyra, Antonia Follenzi, Ekaterina Dadachova, Sepehr Eskandari, L. Mario Amzele, Nancy Carrasco

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

I - uptake in the thyroid, the first step in thyroid hormone biosynthesis, is mediated by the Na +/I - symporter (NIS) with an electrogenic 2Na + : 1I - stoichiometry. We have obtained mechanistic information on NIS by characterizing the congenital I - transport defect-causing NIS mutant G93R. This mutant is targeted to the plasma membrane but is inactive. Substitutions at position 93 show that the longer the side chain of the neutral residue at this position, the higher the K m for the anion substrates. Unlike WT NIS, which mediates symport of Na + and the environmental pollutant perchlorate electroneutrally, G93T/N/Q/E/D NIS, strikingly, do it electrogenically with a 2:1 stoichiometry. Furthermore, G93E/Q NIS discriminate between anion substrates, a discovery with potential clinical relevance. A 3D homology model of NIS based on the structure of the bacterial Na +/galactose transporter identifies G93 as a critical player in the mechanism of the transporter: the changes from an outwardly to an inwardly open conformation during the transport cycle use G93 as a pivot.

Original languageEnglish (US)
Pages (from-to)17933-17938
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number44
DOIs
StatePublished - Nov 1 2011

Keywords

  • Homology modeling
  • Iodide transport defect
  • Radioiodide therapy
  • Sodium solute cotransporter family

ASJC Scopus subject areas

  • General

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    Paroder-Belenitsky, M., Maestas, M. J., Dohán, O., Nicola, J. P., Reyna-Neyra, A., Follenzi, A., Dadachova, E., Eskandari, S., Amzele, L. M., & Carrasco, N. (2011). Mechanism of anion selectivity and stoichiometry of the Na +/I - symporter (NIS). Proceedings of the National Academy of Sciences of the United States of America, 108(44), 17933-17938. https://doi.org/10.1073/pnas.1108278108