The controlled uptake and use of trace metals such as zinc are vital to many molecular mechanisms within the body. Moreover, mapping the molecular structure where medicinal compounds function is a crucial step toward drug discovery against deadly diseases. Now, researchers at Michigan State University (MSU) have taken a vital step forward by providing a crystal structure of the extracellular domain, or ECD, of ZIP4—the exclusive protein responsible for the uptake of zinc from food. The ZIP family consists of thousands of zinc/iron transporter proteins, and this work represents the first-ever structural information of the ZIP family at the atomic level.
This new study helps provide a roadmap of potential target sites for people suffering from acrodermititis enteropathica—a rare but lethal genetic disorder leading to severe zinc deficiency—and pancreatic cancer where ZIP4 is abnormally overexpressed.
“Many drug candidates fail during development because their targets are buried inside the cell,” explained senior study author Jian Hu, Ph.D., assistant professor in the department of chemistry at MSU. “With ZIP4, though, the large ECD is fully exposed to the extracellular space and quite accessible.”
The MSU team revealed that the ZIP4 ECD acts as a critical accessory domain that is essential for optimal zinc transport. The researchers hypothesize that targeting this domain could be a promising strategy to regulate the function of ZIP4.
“We report the first crystal structure of a mammalian ZIP4-ECD, which reveals two structurally independent subdomains and an unprecedented dimer centered at the signature PAL motif,” the authors wrote. “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.”
The results of this study were published recently in Nature Communications in an article entitled “Structural Insights of ZIP4 Extracellular Domain Critical for Optimal Zinc Transport.”
Interestingly, the new study also revealed that many human ZIP proteins share a common architecture in their ECDs—shedding light on structural and functional studies of other ZIP proteins involved in a variety of cancers, osteoarthritis, and other serious diseases. Now investigators have a research foundation on which to further study zinc transport mechanism of ZIP proteins.
“These findings lead to working hypotheses on how ZIP4-ECD exerts critical functions in zinc transport,” the authors penned. “The conserved dimeric architecture in ZIP4-ECD is also demonstrated to be a common structural feature among the LIV-1 proteins.”
Dr. Hu stated that he was drawn to study zinc and other trace elements because they are essential for life, and zinc is the second most common trace element behind iron. Much of his research has focused on deciphering how the body maintains proper levels and what happens when amounts of trace elements rise to toxic levels.
“For example, for patients suffering from diseases like Alzheimer's or Parkinson's, the levels of transition metals, particularly zinc and iron, in their brains are significantly higher than those of healthy people,” Dr. Hu noted. “My laboratory is interested in revealing a better understanding of the body's system of properly handling these trace elements.