Parkinson’s Research Might Benefit from Novel Discovery of Zinc Transport Protein Structure

Researchers at Michigan State University (MSU) are closer than ever to understanding the structure of a protein called ZIP4 – the only factor responsible for the uptake of zinc from food. Although zinc is a mineral essential for numerous bodily processes, unbalanced levels of the element can cause or contribute to conditions such as Parkinson’s disease.

In Parkinson’s, patients often have increased and unhealthy levels of zinc in the brain, but research exploring how zinc levels are regulated, or can be controlled, in the body has been hampered by the lack of insights into the molecular structures zinc transporters, commonly called ZIPs.

But MSU researchers have solved the crystal structure of the protein– a process whereby scientists force proteins into crystal shapes. This allowed them to x-ray the crystals, revealing how the protein looks on an atomic scale. It also may hold the key to developing drugs that could balance the amount of zinc in the body.

“Many drug candidates fail during development because their targets are buried inside the cell,” said Jian Hu, assistant professor in MSU’s chemistry department in a press release.  “With ZIP4, though, the large ECD (extracelluar domain) is fully exposed to the extracellular space and quite accessible.”

ECD protrudes from from the surface of cell.

Revealed in the study “Structural insights of ZIP4 extracellular domain critical for optimal zinc transport,” published in the journal Nature Communications, was part of the ECD essential for zinc transport.

While ZIP4 is the only protein catching zinc as we eat, it belongs to a large family of other ZIPs, or zinc iron permeases, transporting both zinc and iron in other bodily locations. The structures of all other ZIPs are still unknown.

Though focused only on ZIP4, the study gives researchers investigating other ZIP proteins involved in cancers, osteoarthritus and other diseases, a tool to advance their studies. Many human ZIPs have extracellular parts that are very similar to that of ZIP4.

Hu, the senior author of the study, has long been fascinated by zinc as crucial for life and its role in disease.

“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,” Hu said. “My laboratory is interested in revealing a better understanding of the body’s system of properly handling these trace elements.”