A computational study of the structure and function of human Zrt and Irt-like proteins metal transporters: An elevator-type transport mechanism predicted by AlphaFold2

The ZIP (Zrt and Irt-like proteins) protein family includes transporters responsible for the translocation of zinc and other transition metals, such as iron and cadmium, between the extracellular space (or the lumen of organelles) and the cytoplasm. This protein family is present at all the phylogenetic levels, including bacteria, fungi, plants, insects, and mammals. ZIP proteins are responsible for the homeostasis of metals essential for the cell physiology. The human ZIP family consists of fourteen members (hZIP1-hZIP14), divided into four subfamilies: LIV-1, containing nine hZIPs, the subfamily I, with only one member, the subfamily II, which includes three members and the subfamily gufA, which has only one member. Apart from the extracellular domain, typical of the LIV-1 subfamily, the highly conserved transmembrane domain, containing the binuclear metal center (BMC), and the histidine-rich intracellular loop are the common features characterizing the ZIP family. Here is presented a computational study of the structure and function of human ZIP family members. Multiple sequence alignment and structural models were obtained for the 14 hZIP members. Moreover, a full-length three-dimensional model of the hZIP4-homodimer complex was also produced. Different conformations of the representative hZIP transporters were obtained through a modified version of the AlphaFold2 algorithm. The inward and outward-facing conformations obtained suggest that the hZIP proteins function with an “elevator-type” mechanism.