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

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 + :1ClO 4 − ), which competes with I −...

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Veröffentlicht in:Nature structural & molecular biology 2020-06, Vol.27 (6), p.533-539
Hauptverfasser: Llorente-Esteban, Alejandro, Manville, Rían W., Reyna-Neyra, Andrea, Abbott, Geoffrey W., Amzel, L. Mario, Carrasco, Nancy
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Sprache:eng
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Zusammenfassung: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 + :1ClO 4 − ), 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 ClO 4 − transport is due to ClO 4 − binding to a high-affinity non-transport allosteric site that prevents Na + from binding to one of its two sites. Furthermore, low concentrations of ClO 4 − 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 ClO 4 − pollution in drinking water is more dangerous than previously thought. Transport and electrophysiology measurements of the Na + /I − symporter reveal that environmental pollutant perchlorate binds to an allosteric site and inhibits I − transport not only by competition but also by changing the stoichiometry of I − transport.
ISSN:1545-9993
1545-9985
DOI:10.1038/s41594-020-0417-5