Scientists discover the secret to regulating our biological clock

Scientists have discovered a revolutionary way to end jet lag by discovering the secret of casein kinase 1 delta (CK1δ), a protein that regulates our biological clock. This breakthrough, by researchers at Duke-NUS Medical School and the University of California, Santa Cruz, offers a new approach to adjusting our circadian rhythms, the natural 24-hour cycles that influence sleep-wake patterns and overall daily functions.

Published in the journal Proceedings of the National Academy of Sciences (PNAS), their findings could pave the way for new approaches to treating disorders linked to the biological clock.

CK1δ regulates circadian rhythms by marking other proteins involved in our biological clock to fine-tune the timing of these rhythms. In addition to modifying other proteins, CK1δ itself can be marked, thereby altering its own ability to regulate proteins involved in the functioning of the body’s internal clock.

Previous research has identified two distinct versions of CK1δ, known as the δ1 and δ2 isoforms, which vary by just 16 building blocks or amino acids right at the end of the protein in a part called the C-terminal tail. Yet these small differences have a significant impact on CK1δ function. Although it was known that when these proteins are labeled, their ability to regulate the body clock diminishes, no one knew exactly how this happened.

Using advanced spectroscopy and spectrometry techniques to zoom in on the tails, the researchers discovered that how proteins are labeled is determined by their distinct tail sequences.

Professor Carrie Partch, a researcher at the Howard Hughes Medical Institute, Department of Chemistry and Biochemistry at the University of California, Santa Cruz and corresponding author of the study, explained:

“Our results identify three specific sites on the tail of CK1δ where phosphate groups can attach, and these sites are crucial for controlling the activity of the protein. When these points are marked with a phosphate group, CK1δ becomes less active, which which means it doesn’t influence our circadian rhythms as well. Using high-resolution analysis, we were able to identify the exact sites involved, and that’s really exciting.

Having first studied this protein more than 30 years ago while investigating its role in cell division, Professor David Virshup, director of the Cancer and Stem Cell Biology Program at Duke-NUS and co -corresponding author of the study, said: “With the technology we currently have, we have finally been able to get to the bottom of a question that has remained unanswered for more than 25 years.

“We found that the δ1 tail interacts more extensively with the main part of the protein, leading to greater autoinhibition compared to δ2. This means that δ1 is more tightly regulated by its tail than δ2. When these sites are mutated or deleted, δ1 becomes more active, leading to changes in circadian rhythms. In contrast, δ2 does not have the same regulatory effect of its tail region.

This finding highlights how a small portion of CK1δ can greatly influence its overall activity. This self-regulation is essential for maintaining the balance of CK1δ activity, which helps regulate our circadian rhythms.

The study also addressed the broader implications of these findings. CK1δ plays a role in several important processes beyond circadian rhythms, including cell division, cancer development, and some neurodegenerative diseases. By better understanding how CK1δ activity is regulated, scientists could open new avenues to treat not only circadian rhythm disorders, but also a whole range of pathologies.

Professor Patrick Tan, Senior Associate Dean for Research at Duke-NUS, added: “Regulating our internal clock goes beyond curing jet lag: it is about improving sleep quality, metabolism and overall health. This important discovery could potentially open new doors to treatments that could transform the way we manage these essential aspects of our daily lives.

The researchers plan to further study how real-world factors, such as dietary and environmental changes, affect the marking sites on CK1δ. This could provide insights into how these factors affect circadian rhythms and could lead to practical solutions for managing disruptions.