2.A.49.5.1
Cl^-:H⁺ (2:1) antiporter, EriC or ClcA (ClC-ecl) (Accardi and Miller, 2004). The x-ray structure has been determined (PDB 1OTS) Dutzler et al., 2002, 2003). The exchange mechanism involves a conformational cycle of alternating exposure of Cl^- and H⁺ binding sites of both ClC pores to the two sides of the membrane (Miloshevsky et al., 2010). Specific aspects of these conformational changes have been proposed (Wang et al. 2018).  Although the protein is present as a homodimer, a single ClC subunit alone is the basic functional unit for transport, and cross-subunit interaction is not required for Cl^-/H⁺ exchange in ClC transporters (Robertson et al., 2010).  Glu202 is essential for H⁺ symport and is on the H⁺ pathway (Lim et al. 2012).  CLC exchangers have two gates that are coupled through conformational rearrangements outside the ion pathway (Basilio et al. 2014).  The rotation of E148 plays a critical role in defining the Cl^-/H⁺ coupling (Lee et al. 2016). The channel shows conserved re-entrant helix-coil-helix domains (Tsirigos et al. 2017). Proton transport is intrinsically coupled to protein cavity hydration changes and is influenced by the protein environment (Wang et al. 2018). EriC also transports fluoride (F^-) (Baker et al. 2012). Non-polar membrane embedded side-chains in CLC-ec1 play a role in defining dimer stability, but the stoichiometry is contextual to the solvent environment, and L194 is a molecular hot-spot for defining dimerization (Mersch et al. 2021).