More insights into how Vision works

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Image: The research team at PSI: Gebhard Schertler, Head of the Biology and Chemistry Department, with his colleagues Diane Barret and Jacopo Marino (from left to right)
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Image: Paul Scherrer Institute / Markus Fischer

PSI scientists have shed light on an important part of the eye: a protein in the rod cells of the retina that helps us see in weak light. As an ion channel in the cell membrane, the protein is responsible for transmitting the optical signal from the eye to the brain. When a genetic disorder disrupts a person’s molecular function, they go blind. Scientists have deciphered the three-dimensional structure of the protein, paving the way for innovative medical treatments. The study will be published in the scientific journal Nature structural and molecular biology.

“Thanks to the rod cells in our eyes, we can observe the stars in the night sky,” explains Jacopo Marino, biologist at the Laboratory for Biomolecular Research at PSI. “These photocells are so sensitive to light that they can even recognize a single photon reaching us from a very remote part of the universe – a really incredible achievement.” The ability of our brain to ultimately translate these light rays into a visual impression is under Among other things, on the cyclic nucleotide-controlled (CNG) ion channels, the three-dimensional structure of which has now been illuminated by a PSI research group led by Jacopo Marino.

The ion channel acts as a gatekeeper, which controls whether certain particles can be let through into the interior of the receptor cell. It is embedded in the protein-rich shell – the cell membrane – of the rod cells. In the dark, the ion channel and thus the gate to the cell is completely open. But when light hits the eye, it triggers a cascade of processes in the rod cells. This ultimately closes the gate so that positively charged particles, such as calcium ions, can no longer penetrate the cell.

This electrochemical signal continues via the nerve cells into the visual cortex of the brain, where a visual impression – for example a flash of light – is created. “The idea of ​​solving the structure of this channel goes back almost 20 years, when Gebhard Schertler and Benjamin Kaupp were already working together on this topic,” says Jacopo Marino. Both are co-authors of the new study.

Perseverance paid off

PhD student Diane Barret first had to extract the channel protein from the eyes of cows that a slaughterhouse delivers – a complicated and laborious process. “That was a very demanding task because the protein is extremely sensitive and decomposes very quickly. In addition, it is only present in tiny amounts in the starting material, ”explains Barret. It took a full two years to get enough protein to work with. “We were both too stubborn to just give up,” says Jacopo Marino with a laugh. “But this stubbornness paid off in the end.”

The scientists then used cryo-electron microscopy to show the three-dimensional structure of the ion channel. “In contrast to previous studies on the structure of the ion channel, we examined the native protein as it is in the eye. We are therefore much closer to the real conditions that prevail in living beings, ”says Diane Barret.

A better understanding of the natural structure of the channel protein is important, among other things, to advance the development of treatments for genetic diseases for which there is no known cure, such as retinitis pigmentosa. In this disease, the photoreceptors gradually die, making people blind. One possible cause is that the body is unable to properly manufacture the CNG channel protein due to a genetic defect. As a result, the ion channel does not close completely when exposed to light, which disrupts the electrochemical balance of the cell and leads to the death of the cells.

“If we could find molecules that influence the protein in such a way that the channel closes completely, we could prevent the cells from dying – and thus prevent blindness,” explains Jacopo Marino. Now that the researchers have identified the exact structure of the protein, they can search for such molecules in a targeted manner.

Additional barrier

The protein consists of four parts: three batches of subunit A and one batch of subunit B. Only in this combination is a properly functioning ion channel possible. In their study, PSI scientists show why the B subunit seems to play such an important role: A side arm of the protein – a single amino acid – protrudes like a barrier over a gate from the rest of the protein. This narrows the passage in the channel to the point where no ions can pass.

“Nobody expected that – it came as a complete surprise,” says Diane Barret. In sub-unit A there are already other bottlenecks – such as the main portals – which were previously considered the only ones. It is interesting that the additional barrier is not only found in the protein from the cow’s eye, but also appears to apply to all animal species, as the scientists showed. Whether crocodiles, eagles or humans – all living things with an ion channel in their eye have the same outstanding amino acid at this point in the protein. Since it has been so consistently conserved during evolution, it must be essential for the canal to function.

Text: Paul Scherrer Institute / Brigitte Osterath

About PSI

The Paul Scherrer Institute PSI develops, builds and operates large, complex research facilities and makes them available to the national and international research community. The institute’s own research focuses on matter and materials, energy and the environment, and human health. PSI is committed to training future generations. That is why around a quarter of our employees are postdocs, postgraduates or trainees. PSI employs a total of 2100 people, making it the largest research institute in Switzerland. The annual budget is around CHF 400 million. PSI is part of the ETH Domain; other members are the two Swiss Federal Institutes of Technology, ETH Zurich and EPFL Lausanne, as well as Eawag (Swiss Federal University of Water Sciences and Technology) and Empa (Federal Materials Testing Institute). and technology) and WSL (Federal Research Institute for Forests, Snow and Landscape).

Contact

Dr. Jacopo Marino

Laboratory for Biomolecular Research, Structural Biology of Membrane Proteins Group

Paul Scherrer Institute, Forschungsstrasse 111, 5232 Villigen PSI, Switzerland

Telephone: +41 56 310 57 77, email: [email protected] [English, Italian]

Diane Barret

Laboratory for Biomolecular Research, Structural Biology of Membrane Proteins Group

Paul Scherrer Institute, Forschungsstrasse 111, 5232 Villigen PSI, Switzerland

Telephone: +41 56 310 29 33, email: [email protected] [English, French]

Original publication

The structure of the native CNGA1 / CNGB1-CNG channel from retinal rods

Diane CA Barret, Gebhard FX Schertler, U. Benjamin Kaupp, Jacopo Marino

Nature structural and molecular biology, December 30, 2021 (online)

DOI: 10.1038 / s41594-021-00700-8


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