TY - JOUR
T1 - Allosteric regulation of mammalian Na+/I− symporter activity by perchlorate
AU - Llorente-Esteban, Alejandro
AU - Manville, Rian
AU - Reyna-Neyra, Andrea
AU - Abbott, Geoffrey
AU - Amzel, L Mario
AU - Carrasco, Nancy
PY - 2020/5/25
Y1 - 2020/5/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085307093&partnerID=8YFLogxK
U2 - 10.1038/s41594-020-0417-5
DO - 10.1038/s41594-020-0417-5
M3 - Article
SN - 1545-9985
VL - 27
SP - 533
EP - 539
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 6
ER -