Zrt/Irt-like proteins (ZIPs) play fundamental roles in metal metabolism/homeostasis and are broadly involved in numerous physiological and pathological processes. The lack of high-resolution structure of the ZIPs hinders understanding of the metal transport mechanism. We report two crystal structures of a prokaryotic ZIP in lipidic cubic phase with bound metal substrates (Cd²⁺ at 2.7 Å and Zn²⁺ at 2.4 Å). The structures revealed a novel 3+2+3TM architecture and an inward-open conformation occluded at the extracellular side. Two metal ions were trapped halfway through the membrane, unexpectedly forming a binuclear metal center. The Zn²⁺-substituted structure suggested asymmetric functions of the two metal-binding sites and also revealed a route for zinc release. Mapping of disease-causing mutations, structure-guided mutagenesis, and cell-based zinc transport assay demonstrated the crucial role of the binuclear metal center for human ZIP4. A metal transport mechanism for the ZIP from Bordetella bronchiseptica was proposed, which is likely applicable to other ZIPs.

Structural and functional characterization of the extracellular domain of the human CaSR with bound Mg ²⁺ and a tryptophan derivative.

Nickel pincers as enzyme cofactors: Organometallic nickel complexes long synthesized in the laboratory exist naturally in enzymes as well. Desguin et al. determined the structure and metal-binding residues of the Ni-containing active site in bacterial lactate racemase (see the Perspective by Zamble). A dithiodinicotinic acid mononucleotide derivative cofactor binds Ni through sulfur and carbon bonds, resembling synthetic nickel pincer complexes. Genes encoding accessory proteins involved in the synthesis of this cofactor are widely distributed in other bacteria, suggesting its involvement in other enzymes. Science , this issue p. 66 ; see also p. 35

The ZIP zinc transporter family is responsible for zinc uptake from the extracellular milieu or intracellular vesicles. The LIV-1 subfamily, containing nine out of the 14 human ZIP proteins, is featured with a large extracellular domain (ECD). The critical role of the ECD is manifested by disease-causing mutations on ZIP4, a representative LIV-1 protein. Here we report the first crystal structure of a mammalian ZIP4-ECD, which reveals two structurally independent subdomains and an unprecedented dimer centred at the signature PAL motif. Structure-guided mutagenesis, cell-based zinc uptake assays and mapping of the disease-causing mutations indicate that the two subdomains play pivotal but distinct roles and that the bridging region connecting them is particularly important for ZIP4 function. These findings lead to working hypotheses on how ZIP4-ECD exerts critical functions in zinc transport. The conserved dimeric architecture in ZIP4-ECD is also demonstrated to be a common structural feature among the LIV-1 proteins.

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.