Allosteric regulation of mammalian Na+/I symporter activity by perchlorate

Alejandro Llorente-Esteban, Rían W. Manville, Andrea Reyna-Neyra, Geoffrey W. Abbott, L. Mario Amzel, Nancy Carrasco

Research output: Contribution to journalArticle

Abstract

The Na+/I symporter (NIS), the plasma membrane protein that actively transports I (stoichiometry 2Na+:1I) in thyroid physiology and radioiodide-based thyroid cancer treatment, also transports the environmental pollutant perchlorate (stoichiometry 1Na+:1ClO4), which competes with I for transport. Until now, the mechanism by which NIS transports different anion substrates with different stoichiometries has remained unelucidated. We carried out transport measurements and analyzed these using a statistical thermodynamics–based equation and electrophysiological experiments to show that the different stoichiometry of ClO4 transport is due to ClO4 binding to a high-affinity non-transport allosteric site that prevents Na+ from binding to one of its two sites. Furthermore, low concentrations of ClO4 inhibit I transport not only by competition but also, critically, by changing the stoichiometry of I transport to 1:1, which greatly reduces the driving force. The data reveal that ClO4 pollution in drinking water is more dangerous than previously thought.

Original languageEnglish (US)
Pages (from-to)533-539
Number of pages7
JournalNature Structural and Molecular Biology
Volume27
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Llorente-Esteban, A., Manville, R. W., Reyna-Neyra, A., Abbott, G. W., Amzel, L. M., & Carrasco, N. (2020). Allosteric regulation of mammalian Na+/I symporter activity by perchlorate. Nature Structural and Molecular Biology, 27(6), 533-539. https://doi.org/10.1038/s41594-020-0417-5