Researchers give new insight into how circadian rhythms work

There is new hope for treating jet lag, insomnia, and other sleep disorders thanks to recent research from a multidisciplinary team that sheds light on the mechanics underlying circadian rhythms.

There is new hope for treating jet lag, insomnia, and other sleep disorders thanks to recent research from a multidisciplinary team that sheds light on the mechanics underlying circadian rhythms. Fruit flies (Drosophila melanogaster), one of the main creatures used to investigate circadian rhythms, are one of the major organisms utilised by researchers to identify the structure of the circadian rhythm photosensor and its target.

The research, "Cryptochrome-Timeless Structure Reveals Circadian Clock Timing Mechanisms" was published April 26 in Nature. The research focused on fruit fly cryptochromes, key components of the circadian clocks of plants and animals, including humans. In flies and other insects, cryptochromes, activated by blue light, serve as the primary light sensors for setting circadian rhythms. The target of the cryptochrome photosensor, known as "Timeless" (TIM), is a large, complex protein that could not previously be imaged and thus its interactions with the cryptochrome are not well understood.

Circadian rhythms work via what are basically genetic feedback loops. The researchers found that the TIM protein, along with its partner, the Period (PER) protein, act together to inhibit the genes that are responsible for their own production. With suitable delays between the events of gene expression and repression, an oscillation in protein levels is established. This oscillation represents the "the ticking of the clock and seems to be fairly unique to the circadian rhythm," said senior author Brian Crane, the George W. and Grace L. Todd Professor and chair of chemistry and chemical biology in the College of Arts and Sciences.

Blue light, Crane said, changes the chemistry and structure of cryptochrome's flavin cofactor, which allows the protein to bind the TIM protein and inhibit TIM's ability to repress gene expression and thereby reset the oscillation. Much of the hard work of the study went into figuring out how to produce the complex of cryptochrome-TIM so it could be studied, because TIM is such a large, unwieldy protein, Crane said. To achieve their results, first author Changfan Lin, M.S. '17, Ph.D. '21, modified the cryptochrome protein to improve the stability of the cryptochrome-TIM complex and used innovative techniques to purify the samples, making them suitable for high-resolution imaging.

"These new methods allowed us to obtain detailed images of the protein structures and gain valuable insights into their function, said Lin, a Friedrich's Ataxia Research Alliance Postdoctoral Fellow at the California Institute of Technology. "This research not only deepens our understanding of circadian rhythm regulation but also opens up new possibilities for developing therapies targeting related processes." (ANI)

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