Jiang, Tao; Han, Wei; Maduke, Merritt; Tajkhorshid, Emad
Molecular Basis for Differential Anion Binding and Proton Coupling in the CI-/H+ Exchanger CIC-ec1

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 PO43- and SO42- 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-ecl 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-, NO3-, and SCN- display distinct binding coordinations at the Scen site and are hydrated in different manners. Consistent with the observation of differential bindings, CIC-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 NO3- leads to the formation of pseudo-water-wires that are substantially different from the wires formed with Cl-. Binding of SCN-, however, eliminates the water wires altogether. These findings provide structural details of anion binding in CIC-ecl 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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