Structures and zinc ion transport pathways of the human SLC39A family of metal transporters

The SLC39A (ZIP) family of zinc ion transporters play a pivotal role in maintaining zinc homeostasis, which is essential for numerous physiological processes involving enzyme catalysis, protein structure and regulation in signal transduction. This investigation employed AlphaFold3 to predict and analyze the 3D structures of all 14 human ZIP family members and revealed key structural and functional features, including transmembrane domains with eight alpha-helices, extracellular and cytoplasmic domains, dimerization, and zinc ion transport pathways. Unique zinc-binding motifs--composed of histidine, aspartic acid, and glutamic acid--were identified. They facilitate zinc ion attraction, selection, and transport. The findings highlight significant structural diversity in these proteins, with additional alpha-helices, disulfide bonds, and other conserved motifs that together contribute to functional specialization across the ZIP family members. Compared to predictions, which exist only for ZIP4, the models incorporate dimeric structures, rationalize loop conformations, and achieve a higher resolution. The predicted 3D structures offer enhanced insights into zinc ion transport mechanisms and provide a foundation for future research into the structural biology of these proteins and their interacting partners in physiology and pathology.