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First Cellular “Chaperone” For Zinc Has Been Identified by Scientists

"This is the first identified protein that puts zinc into other proteins"

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The latest discovery reveals a key mechanism that all living things use to transport a trace element essential for survival

Zinc is a mineral that, for the most part, goes unnoticed. However, all living organisms require zinc to survive. Many proteins require this trace element to fold into the proper shapes in order to function properly. Zinc is also found in enzyme proteins, which help catalyze chemical events, including several that are essential for cell energy production. People, pets, and plants do not survive in the absence of zinc.

This is one of the reasons why biologists at the Brookhaven National Laboratory of the US Department of Energy are so interested in it.

Zinc is obtained from diet or multivitamin supplements, however, up to 30% of individuals in some regions of the world are zinc deficient, which can result in slower growth, decreased immunological function, neurological diseases, and cancer.

Zinc deficiency is the main cause of sickness and mortality, according to the World Health Organization.

Despite zinc’s essential function, it is unclear how the metal is incorporated into proteins that require it or how our cells react to zinc deprivation.

“We’re looking for ways to grow bioenergy plants—either plants that produce biofuels or whose biomass can be converted into fuel—and doing it on land that is not suitable for growing food crops,” says Brookhaven Lab biologist Crysten Blaby. “So, we’re interested in strategies nature uses to survive when zinc and other micronutrients are lacking.”

Blaby and her colleagues describe one such technique in new research published in the journal Cell Reports: a so-called “chaperone” protein that distributes zinc to where it’s needed, which could be especially useful when zinc is low. Though experts have long assumed the existence of a zinc chaperone, including Blaby, the new study provides the first definitive evidence by identifying a “destination” for its deliveries.

Through a series of biochemical assays and genomics investigations, the team found a zinc-dependent protein that is incapable of functioning without the chaperone. MAP1 is a protein found in a variety of organisms, including yeast, mice, plants, and humans. That means the findings apply not only to plants but also to human health, as zinc deficiency causes growth and developmental problems.

“Our goals are in bioenergy crop sustainability,” the authors write, “but because the proteins we are studying are found nearly everywhere, our research has applications that are very broad.”

Chaperones transport other trace metals, such as nickel and copper, around cells because they can be hazardous. The chaperones stop reactive metals from forming “unwanted associations.” Some trace metals react with oxygen to produce free radicals, which are harmful to cells. Zinc, on the other hand, does not appear to be prone to such harmful relationships.

“Zinc is a relatively harmless metal ion. Since it doesn’t react with oxygen to create reactive oxygen species, we thought maybe it just diffuses to get where it needs to go without the need for a chaperone,” say the authors of the study. However, this did not deter scientists from searching for one.

Professor Valérie de Crécy-Lagard first suggested that members of the CobW protein family were the missing zinc chaperones when Blaby was a PhD student at the University of Florida in the early 2000s.

“My research as part of that group provided evidence that if one exists, it was probably a protein in this family. But to prove that it functions as a zinc chaperone, we needed to identify the destination—the protein it was delivering zinc to,” Blaby explains.

For years, many groups worked on the task but were unable to locate and prove the claimed chaperone’s target.

When Blaby started her research group at Brookhaven in 2016, things took a dramatic turn. She discovered evidence of a connection between a protein in the supposed zinc chaperone family and a protein called methionine aminopeptidase, or MAP1, while mining data on protein interactions that had been uploaded to accessible databases during the previous decade. She discovered the relationship between yeast and humans.

“Whenever you see a conserved protein interaction like that, in very different organisms, it usually means that it’s important,” says Blaby.

It turns out that MAP1 affects a wide range of proteins in the cell, affecting practically all species. Unmodified proteins have troubles if MAP1 isn’t operating. Zinc is required for MAP1 to function.

“The pieces were starting to come together,” Blaby remarks. “Then the real fun started—which was to test our very specific hypothesis: that this protein we’ve come to call ZNG1 (pronounced zing 1) is the chaperone that delivers zinc to MAP1.”

Blaby collaborated with Brookhaven postdoctoral researchers Miriam Pasquini and Nicolas Grosjean, who devised and carried out a series of experiments to prove the point. The paper’s initial authorship is shared by the two.

“This was a really great team to bring together to do both the in vivo and in vitro work needed to finally provide experimental evidence for the function of these proteins,” adds the author.

Grosjean first took off the gene that directs cells how to create ZNG1 using fast-growing yeast cells. If this protein is the chaperone that delivers zinc to MAP1, MAP1 in deletion cells should not function properly.

When zinc is deficient in the environment, the MAP1 function deficiency should worsen.

“When a lot of proteins are competing for limited zinc, that’s a situation where, if there’s a chaperone, it might help choose which of the many zinc-dependent proteins should get this precious resource,” Grosjean adds. When zinc levels are low, the chaperone’s absence should be more noticeable.

The results were as expected: cells lacking the ZNG1 gene showed MAP1 activity abnormalities, and the severity of the deficiency increased in the low-zinc environment.

Pasquini then initiated a study to isolate the two proteins, ZNG1 and MAP1. She first demonstrated that, as expected, MAP1 does not function in the absence of zinc.

After that, she combined MAP1 with zinc-loaded ZNG1. However, no MAP1 activity was detected. Something else, the scientists reasoned, must be lacking.

They established that ZNG1 must be engaged in order to transport its zinc cargo in a series of studies. GTP, an energy molecule, is responsible for the activation.

“What we think happens is that the chaperone binds GTP and has a certain conformation, or shape,” Pasquini explains. “When it releases the energy from GTP, it changes shape. We think that conformational change could be important for binding and releasing zinc .”

Pasquini detected MAP1 activity after adding GTP to the zinc-loaded ZNG1 and MAP1 mixture.

“It’s only after you add the energy molecule that you see evidence of zinc being transferred to MAP1,” she further points out.

These findings confirmed that the long-suspected protein now known as ZNG1 functions as a chaperone to transfer zinc to MAP1.

On larger scale “proteomics” experiments, the team partnered with scientists from the Environmental Molecular Sciences Laboratory, a DOE Office of Science user facility at Pacific Northwest National Laboratory. They also collaborated on computational modeling studies with Estella Yee at Brookhaven Lab’s National Synchrotron Light Source II (NSLS-II), a DOE Office of Science user facility, to better understand the protein complex that develops between the zinc chaperone and MAP1.

“Our in vivo and in vitro experiments were looking at just a couple of players. What proteomics allowed us to do was to see how deleting the zinc transferase gene affects all the proteins—and study the impact those players have on the rest of the cell and organism,” says Blaby.

One of the most significant consequences is that cells can no longer adapt to low zinc levels.

“Cells have evolved so that when zinc concentrations get too low, a group of genes turns on to respond to this change of circumstances. But when you get rid of ZNG1, many of those genes stay turned off,” according to Blaby.

“We are now building upon this foundational work completed in the fast-growing yeast model organism to understand how these proteins and their functions are conserved in bioenergy crops,” Blaby adds. “This work shines a light on a previously unknown strategy that plants use to thrive when zinc is limiting in the soil. Understanding such strategies may help us devise ways to optimize crop productivity and achieve environmentally sustainable bioenergy .”

“The possibility for plants to acquire resilience in low-zinc soils also means that we would be able to exploit non-arable land for growing bioenergy crops, leaving fertile soils dedicated to other agricultural purposes,” Pasquini further adds. “Pushing plant cells to produce more ZNG1 would conceivably enable superior growth on marginal lands depleted in zinc.”

Image Credit: Getty

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