Cryo-EM structures of the zinc transporters ZnT3 and ZnT4 provide insights into their transport mechanisms.

Zinc transporters (ZnTs) act as H/Zn antiporters, crucial for zinc homeostasis. Brain-specific ZnT3 expressed in synaptic vesicles transports Zn from the cytosol into vesicles and is essential for neurotransmission, with ZnT3 dysfunction associated with neurological disorders. Ubiquitously expressed ZnT4 localized to lysosomes facilitates the Zn efflux from the cytosol to lysosomes, mitigating the cell injury risk. Despite their importance, the structures and Zn transport mechanisms remain unclear. We characterized the three-dimensional structures of human ZnT3 (inward-facing) and ZnT4 (outward-facing) using cryo-electron microscopy. By combining these structures, we assessed the conformational changes that could occur within the transmembrane domain during Zn transport. Our results provide a structural basis for a more comprehensive understanding of the H/Zn exchange mechanisms exhibited by ZnTs.