Scientist deciphered the structure of an ion channel from the rod cells of the eye (shown in blue) while it communicates with the protein calmodulin (purple). This interaction is necessary to the function not just of the ion channel in the eye, however also of ion channels in other parts of the body such as the heart. Credit: Paul Scherrer Institute/ Dina Schuster
Exciting new findings shed light on the interaction in between the protein calmodulin and an ion channel in the eye, possibly opening the trick behind our eyes exceptional sensitivity to low light conditions.
Using cryo-electron microscopy and mass spectrometry, a team of researchers from PSI has successfully deciphered the structure of an ion channel in the eye as it communicates with the protein calmodulin– a puzzle that has actually stumped scientists for 30 years. This interaction might describe how our eyes can accomplish such exceptional sensitivity to dim light. The findings have actually been released in the journal PNAS.
When you gaze at the brilliant screen of your phone or computer system, the ion channels in your eyes respond to the light by closing. As a result, calcium ions can no longer traverse the channels situated in the cell membrane, which leads to the improvement of the biochemical signal into an electrical one.
Researchers understood the structure of an ion channel from the rod cells of the eye (shown in blue) while it communicates with the protein calmodulin (purple). Utilizing cryo-electron microscopy and mass spectrometry, a group of scientists from PSI has effectively unraveled the structure of an ion channel in the eye as it communicates with the protein calmodulin– a puzzle that has actually baffled researchers for 30 years. A team led by PSI researcher, Jacopo Marino, has actually now enhanced our understanding of how a tiny protein called calmodulin helps to achieve this, by engaging with ion channels in the rod cells. One year back, the scientists prospered in figuring out the structure of this exact same ion channel, found in the rod cells of a cow retina and similar to the ion channel found in the rod cells of our eyes. “We knew that calmodulin regulates the activity of the channel through subunit B, however which kind of structural changes were happening has actually been a big secret for about thirty years, essentially due to the fact that people were not able to solve the structure of the ion channel.”
Now, the rod cells perform this technique. These are the cells that make our eyes delicate to low levels of light, enabling us to look at the night sky and discover simply a few photons of light from a remote star.
A team led by PSI scientist, Jacopo Marino, has now improved our understanding of how a tiny protein called calmodulin helps to accomplish this, by connecting with ion channels in the rod cells. The team, a collaboration in between groups at PSI, ETH Zurich, and University of Bonn, has illuminated for the very first time the three-dimensional structure of the rod cyclic nucleotide-gated (CNG) ion channel as calmodulin binds.
An important function for calmodulin in the eye
One year ago, the researchers succeeded in understanding the structure of this exact same ion channel, discovered in the rod cells of a cow retina and identical to the ion channel found in the rod cells of our eyes. Rod CNG consists of four subunits, a structure shown lots of other ion channels. A peculiarity of the channel is that three subunits– known as subunit A– are similar, whilst a fourth– subunit B– is different.
Researchers have known for a long period of time that this subunit binds calmodulin. Throughout the animal kingdom, this function is discovered. The precise nature of its role has actually remained unclear. “If something is saved through advancement, its an extremely strong sign that its crucial in some way,” describes Marino. “We understood that calmodulin regulates the activity of the channel through subunit B, but which kind of structural changes were happening has actually been a huge mystery for about thirty years, essentially due to the fact that people were not able to fix the structure of the ion channel.”
Now, the scientists can supply a three-dimensional view of what is really taking place. Through a mix of cryo-electron microscopy and mass spectrometry, they could observe that as calmodulin binds, the ion channel ends up being a bit more compact.
The researchers believe that this is natures method of holding the channels closed. What would the purpose of this be? “We believe its a way to minimize spontaneous channel openings that would cause background noise so that our eyes can be conscious dim light,” says Marino.
Mass spectrometry helps researchers fix a wriggly structure
Getting the structure of calmodulin and the ion channel binding was not easy. The interaction between calmodulin and Rod CNG takes place in a highly versatile region of the channel, where it is free to swing about. You take an image and want to work out from this what the human body shape is.
It was thanks to an opportunity meeting, that the group might pin down this wriggly structure. Ph.D. student Dina Schuster heard a presentation of Marino. “We were prepared to release based upon the cryo-electron microscopy data alone, which left much of the interaction uncertain, when Dina approached me and stated I think I can help you”, he remembers.
Schuster is establishing unique mass spectrometry-based strategies to study protein interactions. These strategies use enzymes to slice proteins into pieces, either in native conditions within parts of the retinal membrane or when chemically crosslinked. The protein pieces, a few of which are joined together, are determined by mass spectrometry. This reveals info on which parts of the protein were close together in three-dimensional space– comparable to piecing together a 3D jigsaw puzzle. “These strategies enabled us to narrow down a few of the possibilities that were ambiguous with cryo-electron microscopy,” describes Schuster, who is joint very first author of the publication together with PhD trainee, Diane Barret.
From the marvel of vision to ramifications in human health
Calmodulin manages ion channels not just in the eye however throughout the body, managing electrical signals that are vital to the correct performance of diverse muscles and organs. Over the last few years, it has emerged that when this interaction goes incorrect due to anomalies in the calmodulin gene, there can be severe health ramifications, such as cardiac failure: something that is not yet completely comprehended.
As assisting our understanding of a most basic wonder– how we can see the stars– the findings of this research study, and approaches used, may assist our understanding of the interaction of calmodulin with ion channels in other parts of the body.
Recommendation: “Structural basis of calmodulin modulation of the rod cyclic nucleotide-gated channel” by Diane C. A. Barret, Dina Schuster, Matthew J. Rodrigues, Alexander Leitner, Paola Picotti, Gebhard F. X. Schertler, U. Benjamin Kaupp, Volodymyr M. Korkhov and Jacopo Marino, 3 April 2023, Proceedings of the National Academy of Sciences.DOI: 10.1073/ pnas.2300309120.
