Fig. 7.

A proposed model of electroneutrality versus electrogenicity. The four main variations of the putative interaction between the conserved polar residues on TM-5 and TM-10 are shown. Helices are numbered according to EcNhaA’s topology. The relevant residues are shown as circles, with acidic in red, basic in blue, and polar in yellow. Interactions that are expected to remain intact throughout the transport cycle according to the proposed model are marked with solid lines in a, c, d, and the interaction that would alternate is marked with a dashed line in b. a The electroneutral CPA1 subtree would feature a salt bridge between arginine in position 8 and glutamate in position 5. The protonation state of these residues would be fixed, while that of D₇ would change upon proton transport. b Electrogenic CPA2s, characterized by acidic residues in positions 6 and 7, presumably interacting with the two protons, and a basic residue in position 8. Upon interacting with a proton, D₆ would alternate between salt bridging and hydrogen bonding with K₈. c Putative electroneutral transport by CPA2s that lack the acidic residue in position 6. Positions 6 and 8 would hydrogen bond with each other. Similar to electroneutral CPA1s, the protonation state of these residues would be fixed, while that of D₇ would alter upon interaction with the proton. d Electroneutral mammalian NHA-like CPA2s, surprisingly featuring two acidic residues at positions 6 and 7, similar to the electrogenic CPA2s shown in b. This group also includes an arginine at position 8 that is prevalent in electroneutral CPAs, and a uniquely conserved glutamate on TM-3 that potentially could salt bridge with each other. This slight change in the dielectric environment of D₆ could, theoretically, prevent its protonation and deprotonation, resulting in electroneutral transport