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Nanotechnology Now – Press Release: Zinc transporters have built-in self-regulatory sensors: New cryo-EM structure of zinc transport proteins reveals how this molecular machinery functions to regulate cellular levels of zinc, an essential micronutrient


Home > Press > Zinc transporters have built-in self-regulatory sensors: New cryo-EM structure of zinc transport proteins reveals how this molecular machinery functions to regulate cellular levels of zinc, an essential micronutrient

The overall structure of the ZIP transmembrane zinc transporter protein determined by cryo-electron microscopy (cryo-EM) (left) and a schematic showing some of the functional features (right). The inward-facing flexible (magenta) ring of cells binds zinc and folds to block more zinc from entering when levels of this micronutrient become too high. CREDITS Brookhaven National Laboratory

Abstract:
Scientists at the US Department of Energy’s (DOE) Brookhaven National Laboratory have determined the atomic-level structure of zinc transporter protein, the molecular machine that regulates levels of this important metal micronutrient in cells. As described in a paper just published in Nature Communications, the structure reveals how cell membrane proteins change their shape to move zinc from the environment into cells, and temporarily block this action automatically when zinc levels in cells become too high.

Zinc transporters have built-in self-regulatory sensors: Novel cryo-EM structures of zinc transport proteins reveal how this molecular machinery functions to regulate cellular levels of zinc, an essential micronutrient

Upton, New York | Posted on June 9, 2023

“Zinc is important for many biological activities, but too much can be problematic,” said Qun Liu, the Brookhaven Lab biophysicist who led the project. “During evolution, various organisms have evolved in many ways to regulate zinc. But no one has shown that the transporters that control zinc uptake from the environment can regulate their activity on their own. Our study is the first to demonstrate a zinc transporter with such a built-in sensor.”

This research was conducted as part of the Brookhaven Lab’s Quantitative Plant Sciences Initiative (QPSI). By using a bacterial version of a zinc transporter that shares important features with zinc transporters in plants, scientists gained important insights into how these proteins work.

“This research is part of our effort to understand how micronutrients like zinc are absorbed by plants so we can understand how to design crops that are better able to grow on marginal lands for bioenergy production,” said Brookhaven Lab Biology Department Chair John Shanklin, co-author on the paper. .

The research may also suggest ways of engineering food crops with increased zinc content to increase their nutritional value, the scientists noted.

Cryo-EM plus computing
To solve the protein structure, the Brookhaven team used cryo-electron microscopy (cryo-EM) at the Laboratory for BioMolecular Structure (LBMS). With this technique, scientists can sample many different conformations of a protein instead of a single crystalline form. That’s important because, in nature, proteins are dynamic, not static; part of them moving around.

“Cryo-EM doesn’t require proteins to form crystals, so we can actually capture dynamic steps that might not be possible using X-ray crystallography, another technique for studying protein structure,” Liu said. “In essence, with cryo-EM, we can capture more frames from the ‘film’ to obtain structures that are very helpful in understanding the biological function of proteins.”

To sort through the wide variety of structures, scientists need powerful computational tools. This includes artificial intelligence approaches that use machine learning, some of which Liu has developed. Using this algorithm, scientists can semi-automatically select and sort millions of cryo-EM images to find groups of structures with similarities. This method allowed them to achieve the highest possible resolution, and thereby reveal the atomic-scale details of the structure.

For this study, this cryo-EM approach revealed a key feature of the one-step zinc transporter ZIP (Zrt-/Irt-like protein) revealing how it regulates its own zinc uptake activity depending on how much zinc is already present in the cell. .

“Our new data led us to revise our previous view of how these proteins work,” said Liu.

Tilt to enter, feel to stop
Previous reports based on x-ray crystallography and coevolution analysis suggest that the carrier may serve as a sort of “elevator” for transporting zinc. New research shows how interactions with zinc on both sides of the cell membrane trigger the movement of protein moieties to carry zinc into cells — and, most importantly, block entry when levels get too high.

“Our primary structure shows that when the zinc level in the cell rises to a certain level—beyond what is needed to meet the cell’s needs—the excess zinc binds to rings on the inside of the membrane,” Liu said. “Then, as this flexible loop changes direction, it folds back on itself, and binds in a way that blocks zinc from entering the cell.”

“It’s almost like a plug goes into the tub drain and blocks it,” adds Shanklin.

Scientists are also figuring out how other parts of the protein move around to allow zinc to enter.

When the zinc level in the cell is low, the zinc falls from the loop section and the plug exits the transporter. Zinc from the environment can move to the transporter. Inside the carrier, the zinc causes parts of the protein machinery to move up and tilt, blocking the exit to the outside environment. Once the zinc moves into the cell, the machine will reset itself to work again.

“Our cryo-EM structure is the first to demonstrate how the circle domain of this protein modulates transporter activity through feedback depending on zinc levels,” said Liu.

It is also the first structure to show that these zinc transporters are composed of two identical proteins—known as dimers. “It takes two molecules to do the job,” Liu said.

Scientists think that having two molecules act in dimers may be related to their function or stability, which they will explore with future computational simulations of how the molecules work together.

“This research could enable new ways to engineer zinc transporters in microbes and plants to optimize their growth under conditions where zinc is too low or too high, potentially on marginal land for the production of bioenergy and bioproducts,” said Liu.

This research was funded by the DOE Office of Science, Office of Biological and Environmental Research (BER) through QPSI, with protein expression, purification, and sample preparation supported by the Office of Basic Energy Sciences (BES). LBMS operations are supported by BER.

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About DOE/Brookhaven National Laboratory
Brookhaven National Laboratory is supported by the US Department of Energy’s Office of Science. The Office of Science is the largest supporter of basic research in the physical sciences in the United States and works to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.

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Contact:
Karen McNulty Walsh
DOE/Brookhaven National Laboratory

Office: 631-344-8350

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Scientific Paper: “Structural Mechanisms of Autoregulation of Intracellular Zinc Uptake in ZIP Transporters”:

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