Researchers from Duke-NUS Medical School and the University of California, Santa Cruz, have uncovered how to manage our internal clock. They discovered that this manager is located at the very end of Casein Kinase 1 delta (CK1δ), a protein that serves as a timer for our body’s biological clock, which regulates our natural 24-hour cycles that influence sleep, wakefulness, and other daily activities known as circadian rhythms.
According to their research published in the journal PNAS, these findings could lead to innovative methods for treating disorders associated with our internal clock.
CK1δ fine-tunes circadian rhythms by tagging other proteins that are crucial for maintaining our biological clock. Additionally, CK1δ can also be tagged, which alters its own capacity to regulate the proteins that manage our body’s internal clock.
Previous studies have identified two different isoforms of CK1δ, named δ1 and δ2, which differ by a mere 16 amino acids located at the C-terminal tail of the protein. Despite their minimal difference, these variations significantly influence CK1δ’s role. Researchers knew that the tagging of these proteins diminishes their regulatory capacity, but the exact mechanism remained unclear.
Employing advanced spectroscopy and spectrometry techniques to investigate the tails of these proteins, the researchers found that the criteria for tagging are dictated by their unique tail sequences.
Professor Carrie Partch, a researcher at the Department of Chemistry & Biochemistry at the University of California, Santa Cruz and the study’s co-author, stated:
“Our results highlight three particular sites on CK1δ’s tail that are key for phosphate group attachment, crucial for regulating the protein’s function. When these sites are phosphorylated, CK1δ’s activity decreases, reducing its effectiveness in controlling our circadian rhythms. Our high-resolution analysis allowed us to identify these specific locations, which is thrilling.”
Professor David Virshup, director of the Cancer and Stem Cell Biology Programme at Duke-NUS and co-author of the study, shared insights from studying this protein over three decades ago during research into its role in cell division:
“Utilizing the technology available now, we finally addressed a question that has remained unanswered for over 25 years. We discovered that the δ1 tail engages more extensively with the core of the protein, leading to stronger self-inhibition compared to δ2. This indicates that δ1 is more closely regulated by its tail than δ2. Altering or removing these sites results in increased activity in δ1, which causes variations in circadian rhythms. Conversely, δ2 does not experience the same regulatory influence from its tail.”
This revelation underscores how a small segment of CK1δ can dramatically affect its entire function. This self-regulation is crucial for maintaining CK1δ’s balanced activity, thereby aiding in the regulation of our circadian rhythms.
The study also explored the broader implications of these results. CK1δ is involved in multiple vital processes beyond circadian rhythms, such as cell division, cancer progression, and specific neurodegenerative diseases. Gaining a deeper understanding of how CK1δ’s activity is controlled could potentially lead to new therapeutic strategies not only for circadian rhythm disorders but also for a variety of other health issues.
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, remarked:
“Managing our internal clock encompasses more than just easing jet lag; it plays a crucial role in enhancing sleep quality, metabolism, and overall health. This significant discovery may open new pathways for treatments that could change how we approach these vital components of our daily lives.”
The researchers aim to examine how real-life factors such as diet and environmental shifts influence the tagging sites on CK1δ. This exploration could shed light on how such factors impact circadian rhythms and might lead to tangible strategies for addressing disruptions.
Duke-NUS stands out as a global leader in medical education and biomedical research, striving for breakthroughs that extend beyond scientific inquiry for the good of our communities. By blending scientific research with practical applications, the School enhances our understanding of common diseases while developing creative new treatment options.
