TCB Publications - Abstract

Tao Jiang, Wei Han, Merritt Maduke, and Emad Tajkhorshid. Molecular basis for differential anion binding and proton coupling in the Cl/H+ exchanger ClC-ec1. Journal of the American Chemical Society, 138:3066-3075, 2016.

JIAN2016-ET Cl$^$/H$^+$ transporters of the CLC superfamily form a ubiquitous class of membrane proteins that catalyze stoichiometrically coupled exchange of Cl$^$ and H$^+$ across biological membranes. CLC transporters exchange H$^+$ for halides and certain polyatomic anions, but exclude cations, F$^$, and larger physiological anions, such as PO$_4^{3}$ and SO$_4^{2}$. Despite comparable transport rates of different anions, the H$^+$ coupling in CLC transporters varies significantly depending on the chemical nature of the transported anion. Although the molecular mechanism of exchange remains unknown, studies on bacterial ClC-ec1 transporter revealed that Cl$^$ binding to the central anion-binding site (S$_{cen}$) is crucial for the anion-coupled H+ transport. Here, we show that Cl$^$, F$^$, NO$_3^$, and SCN$^$ display distinct binding coordinations at the S$_{cen}$ site and are hydrated in different manners. Consistent with the observation of differential bindings, ClC-ec1 exhibits markedly variable ability to support the formation of the transient water wires, which are necessary to support the connection of the two H+ transfer sites (Glu$_{in}$ and Glu$_{ex}$), in the presence of different anions. While continuous water wires are frequently observed in the presence of physiologically transported Cl$^$, binding of F$^$ or NO$_3^$ leads to the formation of pseudo-water-wires that are substantially different from the wires formed with Cl$^$. Binding of SCN$^$, on the other hand eliminates the water wires altogether. These findings provide structural details of anion binding in ClC-ec1 and reveal a putative atomic-level mechanism for the decoupling of H$^+$ transport to the transport of anions other than Cl$^$.

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