Toward unzipping the ZIP metal transporters: structure, evolution, and implications on drug discovery against cancer

Abstract

The Zrt‐/Irt‐like protein (ZIP) family consists of divalent metal transporters, ubiquitous in all kingdoms of life. Since the discovery of the first ZIPs in the 1990s, the ZIP family has been expanding to contain tens of thousands of members playing key roles in uptake and homeostasis of life‐essential trace elements, primarily zinc, iron and manganese. Some family members are also responsible for toxic metal (particularly cadmium) absorption and distribution. Their central roles in trace element biology, and implications in many human diseases, including cancers, have elicited interest across multiple disciplines for potential applications in biomedicine, agriculture and environmental protection. In this review and perspective, selected areas under rapid progress in the last several years, including structural biology, evolution, and drug discovery against cancers, are summarised and commented. Future research to address the most prominent issues associated with transport and regulation mechanisms are also discussed.

A metabolic inhibitor arms macrophages to kill intracellular fungal pathogens by manipulating zinc homeostasis

“…Operationally, the impaired zinc ingress encompassed dysfunction of at least 2, if not all, importers. This conclusion is based on the fact that various ZIPs shuttle zinc in disparate ways (38). At present, the methodology to quantify metal import only permits analysis of total zinc and not the ingress of a single zinc ion.…”

A path toward concurrent biofortification and cadmium mitigation in plant‐based foods

“…By contrast, by selectively editing metal‐coordinating residues in the transporters (Krishna et al ., 2020), variants that possess low affinity toward Cd may be identified. Recent insights into metal sensing and transport mechanisms (Cointry & Vert, 2019; Hu, 2020) provide hints on parts of the proteins to be targeted for alienating Cd from essential nutrient transport functions.…”

“…The inner layer consists of binuclear metal centers (BMCs) composed of two metal‐binding motifs located in the middle of the metal transport pathway in the protein. The BMC is a typical feature of most ZIPs, including those in plants, but ZIPs have huge variations in the metal‐binding residue composition at the BMC, indicating that substrate specificity is tunable (Hu, 2020; Krishna et al ., 2020). In addition to the BMC, residues in TMH‐2 and the loop connecting TMH‐2 and TMH‐3, which perform a gate‐keeping function, are critical for metal selection (Potocki et al ., 2013).…”

“…In general, metal transporters take on at least two conformations, outward‐ and inward‐facing (Bozzi et al ., 2016; Hu, 2020). The protein grabs the metal from the environment in its outward‐facing configuration and then switches to the inward‐facing mode, possibly with intermediate modes, to deliver the metal into the cell.…”

Redundant roles of four ZIP family members in zinc homeostasis and seed development in Arabidopsis thaliana

“…Zn transporters mediate the cellular influx and efflux of Zn. The Zn‐regulated transporter/iron‐regulated transporter (IRT)‐like protein (ZIP) family members have been reported to transport Zn as well as Fe and Mn into the cytoplasm from either outside of cells or intracellular organelles/vesicles (Hu, 2021). The ZIP family was first identified in Arabidopsis thaliana (Eide et al., 1996) and we now know that members of this family are found throughout all domains of life (Hu, 2021).…”