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Fluoride-dependent interruption of the transport cycle of a CLC Cl(−)/H(+) antiporter

Cl(−)/H(+) antiporters of the CLC superfamily transport anions across biological membranes in varied physiological contexts. These proteins are weakly selective among anions commonly studied, including Cl(−), Br(−), I(−,)NO(3)(−), and SCN(−), but appear to be very selective against F(−). The recent...

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Detalles Bibliográficos
Autores principales: Lim, Hyun-Ho, Stockbridge, Randy B., Miller, Christopher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805709/
https://www.ncbi.nlm.nih.gov/pubmed/24036509
http://dx.doi.org/10.1038/nchembio.1336
Descripción
Sumario:Cl(−)/H(+) antiporters of the CLC superfamily transport anions across biological membranes in varied physiological contexts. These proteins are weakly selective among anions commonly studied, including Cl(−), Br(−), I(−,)NO(3)(−), and SCN(−), but appear to be very selective against F(−). The recent discovery of a new CLC clade of F(−)/H(+) antiporters, which are highly selective for F(−) over Cl(−), led us to investigate the mechanism of Cl(−)-over-F(−) selectivity by a CLC Cl(−)/H(+) antiporter, CLC-ec1. By subjecting purified CLC-ec1 to anion transport measurements, electrophysiological recording, equilibrium ligand-binding studies, and x-ray crystallography, we show that F(−) binds in the Cl(−) transport pathway with affinity similar to Cl(−), but stalls the transport cycle. Examination of various mutant antiporters implies a “lock-down” mechanism of F(−) inhibition, in which F(−), by virtue of its unique H-bonding chemistry, greatly retards a proton-linked conformational change essential for the transport cycle of CLC-ec1.