For the first time, researchers have discovered one of the most important molecular devices in our cells using a ‘twist twist elevator’, unraveling the mystery of how it carries vital chemical signals. from one cell to another.
Individual transport grains captured by the cryo-EM (left), the structure dissolved by an average of thousands of these individual grains (middle) and a computer simulation of the glutamate transporter in a lipid ball reveals the for chloride ions (red) (right; image credit, Shashank Pant, University of Illinois at Urbana-Champaign)
An international team of scientists led by the University of Sydney has shaped one of the most important molecular devices in our cells – the glutamate transporter – helping to define how the cells our brains communicate with each other.
Glutamate transporters are tiny proteins on the surface of all our cells that block on and off the chemical signals that play a major role in ensuring that all cell-to-cell ‘conversations’ occur. cell runs smoothly. They are also involved in zero signaling, metabolism and learning and memory.
The researchers accurately captured the transporters using a cryogenic electron microscope (cryo-EM), showing that they look like a ‘complex elevator’ embedded in the cell membrane.
This worldwide discovery opens up a whole range of possibilities – examining whether deficiencies in the carriers were to blame for brain diseases such as Alzheimer’s disease.
The results of the research were published in Nature.
“The first time I saw the image was amazing. He revealed so much about how this carrier works and explained years of previous research, ”said PhD student Ichia Chen, lead author of the study.
Multitasking carrier
The researchers were able to construct the structure of the glutamate transporter, by analyzing thousands of images trapped in a thin layer of ice using cryo-EM, a highly sensitive microscope that conducted this research. able.
Cryo-EM can visualize what is invisible to the naked eye, using electronic behavior to capture images of biological molecules.
The results also confirm the researchers’ suspicion for some time that the glutamate transporters were multifactorial.
Using Cryo-EM, we’ve discovered for the first time just how these carriers can multitask – performing dual actions of mobile chemicals (like glutamate) across the cell membrane while they also allow water and chloride ions to pass through at the same time.
These molecular devices use a complex device, similar to an elevator, to move the cargo across the cell membrane. But they also have an additional function where they can allow water and chloride ions to move across the cell membrane. We’ve been studying these dual functions for a long time, but we could never explain how these carriers have done this so far. Using a combination of techniques involving cryo-EM and computer simulations, we captured this rare state, where we see both actions occur simultaneously. “
Professor Renae Ryan, Lead Author, School of Medical Sciences, Faculty of Medicine and Health Sciences
“Understanding how the molecular devices in our cells work allows us to explain defects in these machines in disease states and it also gives us an idea of how they might We need to target these devices with pharmacotherapy, ”said Dr Ryan.
Key to closing the gap in disease
Accurate mapping of the structure of the glutamate carrier could be a crucial tool for researchers in understanding how our bodies work – and the mechanism behind some diseases.
Deficiencies in the glutamate transporter have been linked to many neurological diseases such as Alzheimer’s disease and stroke.
This includes rare diseases such as episodic ataxia, a disease that affects movement and causes occasional paralysis, caused by uncontrolled leakage of chloride through the glutamate transporter in cells brain.
Understanding the transport structure of glutamate, which controls the normal flow of chloride, could help to design drugs that can plug the chloride channel up into episodic ataxia. ”
Dr. Qianyi Wu, co-lead author
The result of teamwork
The paper was the result of seven years of work by researchers in Australia and the United States.
The work also highlights the importance of the ability of high-resolution microscopy to understand biological processes.
“We are delighted to use the new Glacios Cryo-EM at the University of Sydney’s Microscopy and Microanalysis facility in Sydney. Having access to this ‘in-house’ microscope will accelerate our research and understanding of these important molecular devices, ”said Dr Josep Font, co-lead author of the study.
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Magazine Reference:
Chen, I., et al. (2021) Glutamate transporters have a chloride channel with two hydrophobic gates. Nature. doi.org/10.1038/s41586-021-03240-9.