Fig. 8: Proposed model of Zn²⁺ transport mediated by a protomer of Golgi-resident Zn²⁺/H⁺ antiporter hZnT7.

During its Zn²⁺ transport cycle, an hZnT7 protomer undergoes TM-helix rearrangement and striking His-loop movement, leading to the facilitated Zn²⁺ recruitment from the cytosol to the negatively charged cytosolic cavity. During this process, the exchange of a Zn²⁺-coordinating residue from His164 to His240 takes place. Once Zn²⁺ is bound to the HDHD motif, the IF form converts to the OF form, concomitant with moving away of His70. In the meantime, protons likely enter the luminal cavity to protonate His70 and possibly His240. These conformational changes around the Zn²⁺-binding site likely serve to facilitate the release of Zn²⁺ to the luminal side. The TM helices are presented as tubes; TM1a, TM1b, TM3 and TM6 in gray, TM2 and TM5 in green, and TM4 in yellow. The visible His-loop segment around the C-terminus of TM4 and N-terminus of TM5 is represented by dark blue lines while dashed lines indicate the invisible region of the His-loop. Zn²⁺ is represented by a red sphere. The negatively charged surfaces of the cytosolic cavity in the IF conformation and the Zn²⁺ release gate in the OF conformation are represented by thick red lines. A proton (H⁺) is represented by a green sphere. Note that the CTD, TM loops and another protomer of the hZnT7 homodimer are omitted for simplification. How two protomers interplay each other within the hZnT7 dimer during the Zn²⁺-transport cycle remains elusive. See also Supplementary Fig. 23.