Antiport Mechanism for Cl−/H+ in ClC-ec1 from Normal-Mode Analysis

ClC chloride channels and transporters play major roles in cellular excitability, epithelial salt transport, volume, pH, and blood pressure regulation. One family member, ClC-ec1 from Escherichia coli, has been structurally resolved crystallographically and subjected to intensive mutagenetic, crystallographic, and electrophysiological studies. It functions as a Cl−/H+ antiporter, not a Cl− channel; however, the molecular mechanism for Cl−/H+ exchange is largely unknown. Using all-atom normal-mode analysis to explore possible mechanisms for this antiport, we propose that Cl−/H+ exchange involves a conformational cycle of alternating exposure of Cl− and H+ binding sites of both ClC pores to the two sides of the membrane. Both pores switch simultaneously from facing outward to facing inward, reminiscent of the standard alternating-access mechanism, which may have direct implications for eukaryotic Cl−/H+ transporters and Cl− channels.