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Biological Chemistry

Retina protein may be a magnetic compass for birds

Cryptochrome 4 forms radical pairs that could guide the migration of the European robin

by Mark Peplow, special to C&EN
June 23, 2021 | A version of this story appeared in Volume 99, Issue 24

Photograph of the European robin (Erithacus rubecula)
Credit: Francis C. Franklin/CC-BY-SA-3.0
The European robin (Erithacus rubecula) contains CRY4 proteins in its retina that could help it to navigate by sensing the Earth’s magnetic field.

A protein in the retina of a migratory bird can respond to weak magnetic fields, researchers have found (Nature 2021, DOI: 10.1038/s41586-021-03618-9). The discovery suggests that the protein, cryptochrome 4 (CRY4), may be a biological compass that enables the birds to navigate during long journeys.

“We’ve known that animals have a magnetic sense for at least 50 years, but how they actually sense the Earth’s magnetic field is still a mystery,” says Eric J. Warrant, a neurobiologist at Lund University who studies vision and magnetic sensing in animals, and was not involved in the research. “I would say it’s the last holy grail of sensory physiology, and this paper brings us tantalizingly closer to actually having a solution.”

A scheme showing how electrons move between tryptophan amino acids within a protein and another molecule called flavin adenine dinucleotide.
Credit: Nature
A series of four electron transfers between four tryptophans (Trp) and flavin adenine dinucleotide (FAD) create a magnetically-sensitive radical pair in the protein CRY4.

CRY4 is found in certain photoreceptor cells in birds, and has long been a suspect in the hunt for a biological compass. But there was no proof that CRY4 was sufficiently sensitive to magnetic fields.

To probe the protein’s function, the researchers used bacterial cell cultures to produce stocks of the European robin’s (Erithacus rubecula) version of CRY4. CRY4 binds to a light-sensitive molecule called flavin adenine dinucleotide (FAD), and contains four crucial tryptophan residues that form a conduit between FAD and the protein’s surface.

Using various spectroscopic techniques, the researchers found that blue light excites an electron in FAD, enabling the molecule to pull another electron from a neighboring tryptophan to become a radical anion (FAD•−). More electrons then hop along the chain from one tryptophan to the next in a domino effect, which ultimately leaves the fourth and final tryptophan as a protonated radical cation (TrpH•+).

“Well within 1 nanosecond, you get a radical pair,” says Peter J. Hore at the University of Oxford, who helped to lead the work. In this radical pair (FAD•− and TrpH•+), the unpaired electrons’ spins can either point in opposite directions, known as a singlet state; or in the same direction, called a triplet state. These states can interconvert millions of times per second, and are the very heart of this magnetic sensor.

Both triplet and singlet states can shuffle protons around to form more stable neutral radicals, Trp and FADH. But only molecules in the singlet state can take a different path, relaxing to their original ground states containing no radicals. The researchers found that a magnetic field of a few millitesla shifts the balance between singlet and triplet states, changing the overall yield of proteins containing the neutral radical products. The scientists think that when the protein sports a FADH, it can trigger a signaling cascade within the robin’s sensory system that allows the bird to sense the Earth’s magnetic field.

If the radical pair in CRY4 really is a biological compass, evolution may have optimized the protein to magnify its effect in migratory birds. So the researchers compared the robin’s CRY4 with CRY4 from pigeons and chickens, both non-migratory birds, and confirmed that the robin’s protein did indeed have a much higher magnetic sensitivity.

They also created mutant versions of the robin’s CRY4, swapping each tryptophan in turn for phenylalanine, which blocks electron transfer. This substitution hampered the formation of radical pairs, confirming the importance of the tryptophan chain.

Overall, the experiments show that CRY4 fulfills some major requirements of a biological compass, Warrant says. Not only is the radical pair sensitive to a magnetic field, it also produces sufficient amounts of FADH with long enough lifetimes to potentially generate a sensory signal.

However, several key questions remain unanswered. The experiments used magnetic fields many times larger than the Earth’s paltry 50 microtesla, so it remains to be seen how well CRY4 respond to smaller fields. Still, the scientists were studying randomly oriented proteins in solution—in birds’ eyes, the proteins would likely be fixed and aligned so they could sense the direction of the Earth’s magnetic field, an arrangement that might also make them more sensitive.

To confirm that CRY4 is a biological compass, researchers will also need to show that its radical pairs are at work in living birds, possibly by studying genetically modified robins that lack parts of CRY4’s tryptophan chain.

Finally, it will be important to identify the biochemical processes that carry the information from the radical pair in the retina all the way to a bird’s brain. This could provide important clues about how the animal perceives those signals. “It might be possible that birds actually see the Earth’s magnetic field,” Warrant says.



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