Microscopic Marvels Blue Proteins Hold Key to Molecular On-Off Switches!

Rare Blue Proteins from Cold-Adapted Microbes Could Serve as Prototypes for Molecular On-Off Switches

Imagine the icy landscapes of Greenland, the towering Himalayas, and the frigid groundwater beneath Finland. These seemingly desolate environments harbor an extraordinary secret: unique molecules within cold-loving microorganisms that hold the potential to control brain cell activity. Structural biologist Kirill Kovalev, an EIPOD Postdoctoral Fellow at EMBL Hamburg and EMBL-EBI, is on a mission to unlock the secrets of these molecules.

Kovalev's fascination lies in rhodopsins, vibrant proteins that allow aquatic microorganisms to capture sunlight for energy. "In my work, I search for unusual rhodopsins and try to understand what they do," Kovalev explains. "Such molecules could have undiscovered functions that we could benefit from."

Some rhodopsins have already been adapted as light-activated switches for cellular electrical activity, a technique known as optogenetics. Neuroscientists use this method to precisely control neuronal activity in experiments. Other rhodopsins with enzymatic capabilities could potentially manage chemical reactions using light.

After years of studying rhodopsins, Kovalev stumbled upon a novel and mysterious group of rhodopsins unlike anything he had encountered before.

This discovery, as often happens in science, occurred by chance. While exploring online protein databases, Kovalev noticed an unusual characteristic shared by microbial rhodopsins found exclusively in extremely cold environments, such as glaciers and high-altitude mountains.

"That's weird," he thought. Rhodopsins are typically found in warmer aquatic environments.

These cold-climate rhodopsins were almost identical, despite evolving thousands of kilometers apart. This led Kovalev to believe they were essential for survival in the cold, and he aptly named them "cryorhodopsins."

Kovalev aimed to decipher these cryorhodopsins: their structure, function, and, most importantly, their color.

Color is a crucial property of rhodopsins. Most are pink-orange, reflecting those colors and absorbing green and blue light, which activates them. Scientists are eager to develop a range of colored rhodopsins to control neuronal activity with greater precision. Blue rhodopsins are particularly valuable because they are activated by red light, which penetrates tissues more deeply and non-invasively.

To Kovalev's astonishment, the cryorhodopsins exhibited an unexpected array of colors, including blue. This groundbreaking research was published in the journal Science Advances.

A rhodopsin's color is determined by its molecular structure, which dictates the wavelengths of light it absorbs and reflects. Any alterations to this structure can change the color.

"I can actually tell what's going on with cryorhodopsin simply by looking at its color," Kovalev stated.

Using advanced structural biology techniques, he discovered that the rare structural feature initially observed in the protein databases was the key to the blue color.

"Now that we understand what makes them blue, we can design synthetic blue rhodopsins tailored to different applications," Kovalev explained.

Further experiments with cultured brain cells revealed that cryorhodopsins induced electric currents when exposed to UV light. Interestingly, green light increased cell excitability, while UV/red light reduced it.

According to Tobias Moser, Group Leader at the University Medical Center Göttingen, "New optogenetic tools to efficiently switch the cell's electric activity both 'on' and 'off' would be incredibly useful in research, biotechnology and medicine."

He further added, "For example, in my group, we develop new optical cochlear implants for patients that can optogenetically restore hearing in patients. Developing the utility of such a multi-purpose rhodopsin for future applications is an important task for the next studies."

"Our cryorhodopsins aren't ready to be used as tools yet, but they're an excellent prototype. They have all the key features that, based on our findings, could be engineered to become more effective for optogenetics," Kovalev stated.

Even on a rainy day, cryorhodopsins can detect UV light, as demonstrated by Kovalev's collaborators at Goethe University Frankfurt. They discovered that cryorhodopsins respond to light more slowly than other rhodopsins, suggesting they might act as photosensors, allowing microbes to "see" UV light.

The team used the AI tool AlphaFold to show that five copies of a small protein would form a ring and interact with the cryorhodopsin.

According to their predictions, the small protein sits poised against the cryorhodopsin inside the cell. They believe that when cryorhodopsin detects UV light, the small protein could depart to carry this information into the cell.

"It was fascinating to uncover a new mechanism via which the light-sensitive signal from cryorhodopsins could be passed on to other parts of the cell. It is always a thrill to learn what the functions are for uncharacterized proteins. In fact, we find these proteins also in organisms that do not contain cryorhodopsin, perhaps hinting at a much wider range of jobs for these proteins."

Why cryorhodopsins developed this dual function, and only in cold environments, remains a puzzle.

"We suspect that cryorhodopsins evolved their unique features not because of the cold, but rather to let microbes sense UV light, which can be harmful to them," Kovalev proposed.

"In cold environments, such as the top of a mountain, bacteria face intense UV radiation. Cryorhodopsins might help them sense it, so they could protect themselves. This hypothesis aligns well with our findings."

"Discovering extraordinary molecules like these wouldn't be possible without scientific expeditions to often remote locations, to study the adaptations of the organisms living there," added Kovalev. "We can learn so much from that!"

Kovalev and his team overcame several technical hurdles, including the near-identical structure of cryorhodopsins and their extreme sensitivity to light. Kovalev applied a 4D structural biology approach, combining X-ray crystallography and cryo-electron microscopy with protein activation by light.

"I actually chose to do my postdoc at EMBL Hamburg, because of the unique beamline setup that made my project possible," said Kovalev.

The team had to work in near-total darkness due to the cryorhodopsins' light sensitivity.

Key Takeaways:

• Cryorhodopsins are a unique group of rhodopsins found in cold environments.
• They exhibit a diverse range of colors, including blue.
• They can act as light-activated switches for cellular electrical activity.
• They may function as UV light sensors, helping microbes protect themselves.

More information: Gerrit Lamm et al, CryoRhodopsins: a comprehensive characterization of a group of microbial rhodopsins from cold environments, Science Advances (2025). DOI: 10.1126/sciadv.adv1015. www.science.org/doi/10.1126/sciadv.adv1015

This fascinating research highlights the untapped potential of cold-adapted microorganisms and their unique biomolecules. The discovery of blue cryorhodopsins as potential molecular on-off switches opens exciting new avenues for optogenetics, biotechnology, and medicine. It serves as a powerful reminder that some of the most groundbreaking scientific advancements can be found in the most unexpected and challenging environments, waiting for curious minds to uncover their secrets. The potential applications stemming from this research are vast, promising innovations in how we understand and manipulate cellular processes.

Source: https://phys.org/news/2025-07-rare-blue-proteins-cold-microbes.html