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 −...
Gespeichert in:
Veröffentlicht in: | Nature structural & molecular biology 2020-06, Vol.27 (6), p.533-539 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
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 |