Scientists from Duke-NUS Medical School and the University of California, Santa Cruz, have discovered the secret to regulating our internal clock. They identified that this regulator is located right at the end of casein kinase 1 delta (CK1δ), a protein that sets the pace of our internal biological clock or the natural 24-hour cycles that control sleep-wake patterns and other daily functions. , known as circadian rhythm.
Published in the magazine PNASTheir findings could pave the way for new approaches to treating disorders related to our biological clock.
CK1δ regulates circadian rhythms by tagging other proteins involved in our biological clock to adjust 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 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. However, these small differences significantly affect CK1δ function. While it was known that when these proteins are marked, their ability to regulate the biological clock decreases, no one knew exactly how this happened.
Using advanced spectroscopy and spectrometry techniques to expand the tails, the researchers discovered that the way proteins are labeled is determined by their different tail sequences.
Howard Hughes Medical Institute Research Professor Carrie Partch, Department of Chemistry and Biochemistry, University of California, Santa Cruz, and corresponding author of the study, explained:
“Our findings point to three specific sites on the tail of CK1δ where phosphate groups can bind, and these sites are crucial for controlling the activity of the protein. When these sites are tagged with a phosphate group, CK1δ becomes less active, resulting in which means it doesn’t influence our circadian rhythms. Also 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 Duke-NUS Cancer and Stem Cell Biology Program and co-corresponding author of the study, explained:
“With the technology we have now, we were finally able to get to the bottom of a question that has been 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 in 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 from its region. line.”
This discovery highlights how a small part of CK1δ can greatly influence its overall activity. This autoregulation is vital to keeping CK1δ activity balanced, which, in turn, 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 certain neurodegenerative diseases. By better understanding how CK1δ activity is regulated, scientists could open new avenues for treating not only circadian rhythm disorders but also a variety of conditions.
Professor Patrick Tan, Senior Vice Dean for Research at Duke-NUS, commented:
“Regulating our internal clock goes beyond curing jet lag: it’s about improving sleep quality, metabolism and overall health. This important discovery could open new doors to treatments that could transform the way we manage these aspects essential to our daily lives.
The researchers plan to further investigate how real-world factors, such as diet and environmental changes, affect marking sites on CK1δ. This could provide insight into how these factors affect circadian rhythms and could lead to practical solutions for managing disruptions.
Duke-NUS is a global leader in medical education and biomedical research, driving advances beyond scientific exploration for the benefit of our communities. By fusing scientific research with translational methods, the School deepens our understanding of prevalent diseases and develops innovative new treatment approaches.