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30-Year-Old Eye Mystery Solved – Ion Channel Structure Deciphered

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Researchers deciphered the structure of an ion channel from a rod cell in the eye (shown in blue) that interacts with the protein calmodulin (purple). This interaction is important not only for ion channels in the eye, but also for the function of ion channels in other parts of the body, such as the heart. Credit: Paul Scherrer Institute / Dina Schuster

An exciting new discovery sheds light on the interaction between the protein calmodulin and ion channels in the eye, and may unlock the secrets behind our eyes’ extraordinary sensitivity to low-light conditions.

Using cryo-electron microscopy and mass spectrometry, a team of researchers at PSI has successfully elucidated the structure of ion channels in the eye as they interact with the protein calmodulin. This is the puzzle that has haunted the scientist for his 30 years. This interaction may explain how our eyes achieve such great sensitivity to dim light.The survey results were published in a magazine PNAS.

Staring at a bright cell phone or computer screen closes the ion channels in your eyes to respond to light. This action represents the culmination of a biochemical chain reaction initiated by exposure to light. As a result, calcium ions cannot pass through channels in the cell membrane, converting biochemical signals into electrical signals. This signal travels through the nervous system and finally reaches the brain for processing.

The same process happens when you stand outside at night and look up at the sky. Well, rod cells do the trick. These are the cells that make our eyes sensitive to low levels of light, allowing us to see the night sky and detect just a few photons of light from distant stars. But this is an amazing feat.

A team led by PSI scientist Jacopo Marino has developed a better understanding of how a small protein called calmodulin can help achieve this by interacting with ion channels in rod cells. . Calmodulin is a calcium sensor. It allows cells to respond to calcium fluctuations. This is one of the universal means of cell communication. A collaborative research team between groups at PSI, ETH Zurich, and the University of Bonn has elucidated for the first time his three-dimensional structure of a rod cyclic nucleotide-gated (CNG) ion channel upon calmodulin binding.

Important Functions of Calmodulin in the Eye

A year ago, researchers successfully deciphered the structure of this same ion channel found in the rod cells of the bovine retina, which is identical to the ion channel found in the rod cells of our eyes. Rod CNG is composed of four subunits and this structure is shared with many other ion channels. However, the specificity of the channel is that his three subunits, known as subunit A, are identical, while the fourth subunit B is different.

Scientists have long known that this subunit binds to calmodulin. However, the exact nature of that role remains unclear. “If something is conserved by evolution, it’s a very strong indicator that it’s important in some way,” Marino explains. “Although we knew that calmodulin regulates channel activity through subunit B, what kind of structural changes occurred was a big mystery for about 30 years. was unable to elucidate the structure of the ion channel.”

Now researchers can see what’s really going on in three dimensions. By combining cryo-electron microscopy and mass spectrometry, we were able to observe that the ion channel becomes a bit more compact when calmodulin is bound.

Researchers believe this is nature’s way of keeping the channel closed. What could be the purpose of this? “We see this as a way to reduce the spontaneous channel opening that causes background noise, making our eyes more sensitive to dim light,” says Marino. say.

Mass spectrometry helps researchers unravel undulating structures

Obtaining calmodulin’s structure and ion channel binding has not been easy. The interaction between calmodulin and rod-CNG occurs in a highly flexible region of the channel where it can swing freely. In cryo-electron microscopy, this makes it very difficult to obtain high-resolution structural information. Here Marino says, “Imagine you have a room of people dancing. You might know, but when your limbs are swaying all over the place, your legs and arms become blurry.”

It was only by chance that the team was able to track down this undulating structure. Her PhD student, Dina Schuster, listened to Marino’s presentation. Many of the interactions were left obscure because she was prepared to publish based solely on cryo-electron microscopy data. I think we can,” she said.

Schuster is developing a new mass spectrometry-based strategy for studying protein interactions. These techniques use enzymes to chop proteins into fragments either in their native state within a portion of the retinal membrane or when chemically cross-linked. Partially bound protein fragments are identified by mass spectrometry. This reveals information about which parts of the protein are close together in her three-dimensional space. This is equivalent to piecing together a 3D jigsaw puzzle. “These techniques allowed us to narrow down some of the possibilities that were ambiguous with cryo-electron microscopy,” says Schuster, co-lead author of the publication with PhD student Diane Barrett. explains.

From visual wonders to impact on human health

Calmodulin regulates ion channels throughout the body, not just the eye, controlling electrical signals that are essential for the proper functioning of various muscles and organs. In recent years, it has become clear that mutations in the calmodulin gene can disrupt this interaction and lead to serious health consequences, such as heart failure, but this is still not fully understood. yeah.

The findings and methods used in this study not only help us understand the most fundamental wonder of how we see stars, but also help us understand the interaction of calmodulin with ion channels in other parts of the body. may be useful for

References: Diane CA Barret, Dina Schuster, Matthew J. Rodrigues, Alexander Leitner, Paola Picotti, Gebhard FX Schertler, U. Benjamin Kaupp, Volodymyr M. Korkhov, “Structural basis for calmodulin modulation of rod-cyclic nucleotide-gated channels.” Jacopo Marino, 3 April 2023, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2300309120

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