All living things, including humans, need zinc in their diet. Too little of this essential metal can disrupt growth and lead to immune system disorders, neurological disorders and cancer. Unfortunately, more than 17% of the world’s population is at risk of zinc deficiency. The World Health Organization considers such micronutrient malnutrition to be a major cause of disease and death.
After you eat, your body’s cells absorb zinc. Inside each cell, zinc binds to proteins to support their structure and function. Scientists estimate that up to 10% of all proteins require zinc to function properly. In this sense, a zinc protein without zinc is like a car without an engine or without the bolts that hold it in place: it can either not work or completely fall apart.
Despite zinc’s importance to human health, some aspects of how it supports cellular processes are not fully understood, including how it is incorporated into proteins essential for cellular function.
As scientists studying how metals work in biological systems like the human body, we wanted to understand how zinc is distributed within the cell. Which cell proteins receive zinc first, especially if zinc is deficient? How does zinc get into these important proteins?
With colleagues in the Skaar lab at Vanderbilt University Medical Center and the Giedroc lab at Indiana University in 2022. we have identified the first known molecule that delivers zinc to key proteins.
Delivering zinc where it is needed
We started by studying the molecules that the cell produces when zinc levels are low. One family of proteins seemed particularly interesting because it appeared to be a potential metallochaperone, a protein that selectively inserts metals such as zinc and iron into other proteins. We named this protein family ZNG1.
As it turns out, all vertebrates have a gene that directs cells to produce ZNG1. Although ZNG1 interacts with several zinc-binding proteins, one protein called METAP1 caught our attention. METAP1 is known to activate many other essential proteins in the cell. Cells without functioning METAP proteins cannot survive.
We were intrigued by METAP1 because it interacts with ZNG1 proteins in a variety of species, including zebrafish, mice, and humans. The finding shows that the connection between the two proteins has persisted for more than 400 million years of evolution, implying that the supportive role of ZNG1 in METAP1 function is important in all organisms that produce these proteins.
To investigate the role of ZNG1 in animal health, we mutated the gene encoding ZNG1 in mice and zebrafish. When ZNG1-deficient animals were deprived of zinc, they either failed to grow or showed developmental defects. Although the animals still have small amounts of zinc, they were unable to utilize the zinc properly. This confirmed that ZNG1 helps METAP1 function properly, likely by helping it bind to or use zinc.
Using molecular imaging and other methods, we also observed that the energy-producing mitochondria of cells from zinc-starved mice did not function properly without functional ZNG1 proteins. This highlights the importance of ZNG1 during periods of zinc deficiency as it helps cells distribute trace amounts of this essential metal to mitochondria and ultimately support cellular energy production.
ZNG1 may be the key to zinc deficiency
We believe that this study is only the first step toward a better understanding of how zinc metallochaperones support health and cellular function when zinc levels are low.
We believe that ZNG1 supports the function of additional zinc-dependent proteins in the cell. In this way, ZNG1 would be a gatekeeper that distributes zinc to a network of key proteins, ultimately allowing the organism to survive even when dietary zinc is limited.
This research paves the way for understanding how cells use zinc during periods of malnutrition or zinc deficiency. Further studies on the proteins that ZNG1 favors for zinc when zinc is insufficient could help determine which cellular processes are most important for sustaining life when zinc is limited. This, in turn, could help combat the negative health consequences of zinc deficiency.
This article is republished from The Conversation, a not-for-profit independent news organization that provides facts and sound analysis to help make sense of our complex world. Posted by Andy Weiss, Vanderbilt University and Caitlin Murdoch, Vanderbilt University
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Andy Weiss receives funding from an American Heart Association Postdoctoral Fellowship and National Institutes of Health T32 and F32 grants.
Caitlin Murdoch receives funding from National Institutes of Health T32 and F32 grants