Fig. 4

Model structure of HsNHA2. Left: periplasmic view, colored by the ConSurf evolutionary conservation bar at the bottom. The dimerization domain is on the left and core domain on the right. Right: close-up view of the unique polar interaction between TM-3, TM-5, and TM-10 characteristic of HsNHA2-like PCAs. The three residues involved are highly conserved. E215 could potentially salt bridge with R432₈ on TM-10. In one plausible scenario D278₆ would be protonated and hydrogen bonded to R432₈, leaving only D279₇ to alternate its protonation state upon transport, resulting in electroneutral transport. Modeling is based on the structure of TtNapA (PDB id 5BZ2) as template