Zinc transporter key to fighting pancreatic cancer and more

September 6, 2017 by Layne Cameron, Michigan State University
Jian Hu and a team of MSU scientists have revealed a key structure of a molecular machine, a ZIP zinc transporter. Credit: MSU

When trace elements rise to toxic levels, bad things happen.

Patients suffering from Alzheimer's and Parkinson's disease harbor significantly higher levels of zinc and iron in their brains than healthy patients. Those with have an unusually high amount of a specific zinc transporter. So, controlling those levels could be an effective plan of attack against these diseases and others, said Jian Hu, Michigan State University biochemist.

Hu and a team of MSU scientists have revealed a key structure of a molecular machine, a ZIP zinc transporter. Mapping the core of a bacterial ZIP - another celebrated first by Hu's lab - exposes its framework and mechanisms that are common in the ZIP family consisting, which comprises thousands of metal transporters.

The human genome encodes a total of fourteen ZIPs, and many of them are associated with diseases. The discovery, published in the current issue of Science Advances, gives pharmaceutical companies targets to test new drugs.

"ZIP4 is aberrantly overexpressed in pancreatic cancer cells, but it's not present in normal pancreatic tissue," Hu said. "This, and knowing that ZIP4 mutations also lead to a lethal genetic disorder, makes ZIP4 a prime drug target that could possibly help patients suffering from many diseases."

The , Acrodermatitis Enteropathica, is a rare but lethal condition caused by severe zinc deficiency. An earlier discovery by Hu's lab revealed the exterior of ZIP4's structure, or its extracellular domain, which functions as an accessory that makes the machinery more efficient.

"But without knowing the structural information of the core, we don't exactly know how the accessory works," Hu said. "We now see that the transmembrane domain is the core of the machine conducting zinc transport."

The team's structure reveals an unprecedented fold for membrane transporters, implying a unique transport mechanism.

"This distinguishes the ZIP family from any other known transporter family," Hu said.

Solving the crystal structure also led to a surprise finding. Examining the molecular architecture revealed two metal ions trapped halfway through the membrane, forming a binuclear metal center.

"It is quite unusual because it resembles the catalytic centers of some metalloenzymes, but apparently the ZIPs are not enzymes," Hu said. "Clarifying the function of the binuclear metal center is one of our primary goals in future studies."

Hu has dedicated much of his career studying and other trace elements, as they are essential for life. Zinc is the second most-common trace element behind iron. By deciphering how the body maintains proper levels and exploring the effects when those elements go awry, he's hoping to unlock the mechanisms of human ZIP's secrets in their many critical roles.

"In the long run, we hope our study will contribute to the discovery of the ZIP inhibitors for pancreatic cancer and other devastating diseases," Hu said.

Explore further: Molecular map provides clues to zinc-related diseases

More information: Tuo Zhang et al. Crystal structures of a ZIP zinc transporter reveal a binuclear metal center in the transport pathway, Science Advances (2017). DOI: 10.1126/sciadv.1700344

Related Stories

Zinc transporters regulate pancreatic cancer

November 12, 2007

Zinc, an important trace element for healthy growth and development, can be related to pancreatic cancer. Too much ZIP4, a molecule that enables the transport of zinc into cells, promotes the growth and spread of pancreatic ...

A link between zinc transport and diabetes

September 24, 2013

Individuals with a mutation in the gene encoding a zinc transporter, SLC30A8 have an elevated risk of developing type 2 diabetes. Insulin granules that are released from pancreatic β cells contain high levels of zinc; however, ...

Recommended for you

Detecting metabolites at close range

June 22, 2018

A novel concept for a biosensor of the metabolite lactate combines an electron transporting polymer with lactate oxidase, which is the enzyme that specifically catalyzes the oxidation of lactate. Lactate is associated with ...

CryoEM study captures opioid signaling in the act

June 22, 2018

Opioid drugs like morphine and fentanyl are a mainstay of modern pain medicine. But they also cause constipation, are highly addictive, and can lead to fatal respiratory failure if taken at too high a dose. Scientists have ...

Researchers achieve unprecedented control of polymer grids

June 21, 2018

Synthetic polymers are ubiquitous—nylon, polyester, Teflon and epoxy, to name just a few—and these polymers are all long, linear structures that tangle into imprecise structures. Chemists have long dreamed of making polymers ...

Template to create superatoms could make for better batteries

June 21, 2018

Virginia Commonwealth University researchers have discovered a novel strategy for creating superatoms—combinations of atoms that can mimic the properties of more than one group of elements of the periodic table. These superatoms ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.