Abstract
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−,NO3−, 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.
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