The Histidine-rich Loop in the Extracellular Domain of ZIP4 Binds Zinc and Plays a Role in Zinc Transport.

The Histidine-rich Loop in the Extracellular Domain of ZIP4 Binds Zinc and Plays a Role in Zinc Transport. Biochem J. 2019 Jun 04;: Authors: Zhang T, Kuliyev E, Sui D, Hu J Abstract The Zrt-/Irt-like protein (ZIP) family mediates zinc influx from extracellular space or intracellular vesicles/organelles, playing a central role in systemic and cellular zinc homeostasis. Out of the 14 family members encoded in human genome, ZIP4 is exclusively responsible for zinc uptake from dietary food and dysfunctional mutations of ZIP4 cause a lethal genetic disorder, Acrodermatitis Enteropathica (AE). About half of the missense AE-causing mutations occur within the large N-terminal extracellular domain (ECD), and our previous study has shown that ZIP4-ECD is crucial for optimal zinc uptake but the underlying mechanism has not been clarified. In this work, we examined zinc binding to the isolated ZIP4-ECD from Pteropus Alecto (black fruit bat) and located zinc binding sites with low micromolar affinity within a histidine-rich loop ubiquitously present in ZIP4 proteins. Zinc binding to this protease-susceptible loop induces a small and highly localized structural perturbation. Mutagenesis and functional study on human ZIP4 by using an improved cell-based zinc uptake assay indicated that the histidine residues within this loop are not involved in preselection of metal substrate but play a role in promoting zinc transport. The possible function of the...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research