2.A.5.4.1
Zip4 dietary Zn²⁺ uptake transporter of 647 aas and 7 TMSs in a 1 (N-terminus) +3 (middle) +3 (C-terminal) TMS arrangement (Acrodermatitis enteropathica zinc-deficiency disease protein) (Dufner-Beattie et al., 2003).  The large cytoplasmic loop is an intrinsically disordered zinc binding domain (Bafaro et al. 2015). A modeled ZIP4 dimer possibly resembles the twelve TMS monomeric PiPT of the MFS, as a likely structural homologue (Antala et al. 2015). Zip4 zinc transporter mutations linked to acrodermatitis enteropathica disrupt function and cause mistrafficking (Kuliyev et al. 2021). A missense variant of SLC39A4 (Zip4) is found in a litter of turkish van cats with acrodermatitis enteropathica (Kiener et al. 2021). hZIP4 is the primary Zn²⁺ importer in the intestine, but it is also expressed in a variety of organs such as the pancreas and brain. It and a mutant form have been expressed in yeast (Liu et al. 2022). The transmembrane domains mediate oligomerization of the human ZIP4 transporter in vivo (Liu et al. 2022).  A "divide and conquer" strategy has been applied to ZIP4 to study the extracellular domain (ECD) and the transmembrane domain separately, which has led to the first ECD structure in the entire ZIP family. Duan and Zhang 2023 provided detailed protocols for the expression, purification, and crystallization of ZIP4-ECD from a mammalian species.  Xenotransplanted human organoids identify transepithelial zinc transports, SLC39A4 and A5, as two mediators of intestinal adaptation (Sampah et al. 2024).