Twisty molecular elevator

How do brain cells talk to each other? With machines, of course.

A team, led by Ichia Chen of the University of Sydney, has modelled the shape of an extremely important molecular machine – the glutamate transporter. Understanding this shape and process helps to explain how brain cells “talk” to each other.

Cells communicate by sending chemical signals, mostly in the form of the neurotransmitter glutamate. These glutamate signals are released from a nerve through glutamate transporters, which sits on the surface of the cell and open and close to let the signal through at the right time, pumping the glutamate out when open.

Because glutamate is such an important neurotransmitter, recognising shapes in the glutamate transporters could provide insights about why and how cells stop talking correctly in the brains of people experiencing Alzheimer’s disease.

The team captured the shape of the transporter in incredible detail with cryogenic electron microscopy (cryo-EM), and found that it looked like a “twisting elevator” inside the cell membrane, they report in their paper, published in Nature.

“The first time I saw the image was amazing,” says Chen. “It revealed so much about how this transporter works and explained years of previous research.”

Image process credit shashankpant
Individual transporter particles captured by the cryo-EM (left), the structure solved by averaging thousands of these individual particles (middle) and a computer simulation of the glutamate transporter in a lipid membrane revealing the pathway for chloride ions (red). Credit: Shashank Pant, University of Illinois at Urbana-Champaign

The team were able to build their model by analysing thousands of images that were inside an exceedingly thin layer of ice, using the cryo-EM. This makes infinitesimally small things visible by using electron beams to take the photo.

The images showed that the glutamate transporter could multi-task. The first function was to pump glutamate through the membrane and the second is to transport other molecules.

“These molecular machines use a really cool twisting, elevator-like mechanism to move their cargo across the cell membrane,” says senior author Renae Ryan, from the University of Sydney.

“But they also have an additional function where they can allow water and chloride ions to move across the cell membrane.

“We have been studying these dual functions for quite some time, but we could never explain how the transporters did this until now.”

The twisting elevator mechanism of the glutamate transporters activates a chloride channel. After the gate (red) closes, the transport domain (blue) moves relative to the scaffold domain (brown) towards the inside of the cell. During this transport process, a pore opens up that allows water and chloride ions to move through in the chloride conducting state.

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