Scientists discover a protein that plays a key role in regulating the body’s internal clock

Medical News: A breakthrough in treating jet lag and sleep disorders
A group of researchers from Duke-NUS Medical School in Singapore and the University of California, Santa Cruz-USA, has made a significant discovery in the world of circadian rhythm research. They uncovered how a protein called Casein Kinase 1 delta (CK1δ) regulates our body’s internal clock. This discovery could pave the way for new treatments for issues like jet lag and other disorders related to our biological rhythms. The results are detailed in this Medical News report and shed light on how the manipulation of CK1δ could lead to better management of sleep patterns and even certain diseases.


A peptide (shown in mesh) with attached phosphate tags (red and orange spheres) blocks the active site of CK1δ. Tagging the tail end of CK1δ, a process known as auto-phosphorylation, makes the protein less active, and with that less able to fine-tune the body’s internal clocks. // Credit: Jon Philpott, Rajesh Narasimamurthy and David Virshup

How CK1δ Regulates the Body’s Biological Clock
Our body’s internal clock, also known as the circadian rhythm, controls many vital processes such as sleep-wake cycles, metabolism, and hormone release. At the core of this clock are proteins that interact with one another to keep our body functioning on a roughly 24-hour cycle. Among these proteins is CK1δ, which plays a crucial role in regulating the timing of these cycles by tagging other proteins with phosphate groups. These phosphate tags act like signals that modify how these proteins function, ultimately influencing the overall rhythm of the body.
 
Interestingly, CK1δ also has the ability to regulate itself through a process known as autophosphorylation, where it tags its own protein structure. This self-regulation is central to CK1δ’s function and has a significant impact on how effectively it can control the body’s internal clock. The study team from Duke-NUS and the University of California set out to understand how this self-tagging process works and what effect it has on CK1δ's role in regulating circadian rhythms.
 
Two Versions of CK1δ: Small Differences, Big Impact
The researchers identified two slightly different versions of CK1δ, referred to as isoforms δ1 and δ2. These versions differ by only 16 amino acids in their structure, yet these tiny differences lead to significantly different behaviors in terms of how they regulate the body’s biological clock. Isoform δ1, for instance, is more tightly regulated by its structure compared to δ2. This means that δ1 is less active and plays a more controlled role in regulating circadian rhythms, whereas δ2 has less self-regulation and is more active.
 
The key to these differences lies in a part of CK1δ called the C-terminal tail. This tail is where phosphate groups can attach, modifying the activity of the protein. Using advanced techniques such as spectroscopy and mass spectrometry, the researchers were able to pinpoint three specific sites on this tail where phosphate groups bind. When these sites are tagged, CK1δ’s ability to regulate circadian rhythms is diminished.
 
Professor Carrie Partch from the University of California, Santa Cruz, explained the significance of this discovery: “Our findings pinpoint three specific sites on CK1δ’s tail where phosphate groups can attach, and these sites are crucial for controlling the protein’s activity. When these spots get tagged with a phosphate group, CK1δ becomes less active, which means it doesn’t influence our circadian rhythms as effectively.”
 
Implications for Treating Circadian Disorders and Diseases
Beyond its role in circadian rhythms, CK1δ is involved in other important processes such as cell division and even the development of certain diseases like cancer and neurodegenerative disorders. By better understanding how CK1δ’s activity is regulated, scientists believe they can unlock new methods for treating not just circadian rhythm disorders but also a wide range of conditions.
 
This discovery has the potential to revolutionize how we approach treatments for common issues like jet lag, sleep disorders, and even more serious health concerns related to circadian disruptions. Jet lag, for instance, occurs when our body’s internal clock is out of sync with the local time zone, making it difficult to adjust to new sleep patterns. With the knowledge gained from this research, scientists could develop new ways to reset our internal clocks, helping people adapt more quickly to time changes and reducing the negative health impacts of disrupted sleep cycles.
 
Professor David Virshup, from Duke-NUS Medical School, highlighted the broader applications of the study: “With the technology we have now, we were finally able to answer a question that has gone unanswered for over 25 years. This discovery opens the door for us to explore new treatments for circadian rhythm disorders and possibly other conditions where CK1δ plays a role.”
 
How Lifestyle Factors Could Influence CK1δ Activity
The researchers also plan to investigate how real-world factors like diet, light exposure, and environmental changes might influence CK1δ activity. Since our circadian rhythms are sensitive to these external factors, understanding their effects on CK1δ could lead to practical solutions for managing disruptions in sleep and overall health.’
 
Diet, in particular, is an area of interest, as it has been shown to have a significant impact on the body’s internal clock. By studying how different foods or nutrients affect CK1δ’s tagging process, scientists hope to find dietary interventions that could help people maintain better circadian rhythms, especially those with irregular schedules such as shift workers.
 
Similarly, light exposure is known to be a powerful regulator of circadian rhythms. The researchers are interested in how varying light conditions, such as those experienced during seasonal changes, might alter CK1δ’s activity and whether interventions like light therapy could help regulate circadian rhythms more effectively.
 
Looking Ahead: Potential for New Treatments
The discovery of CK1δ’s self-regulating mechanism is just the beginning of what could be a new era in circadian rhythm research. The researchers are excited about the potential applications of their findings, which could extend beyond sleep disorders to other health issues such as metabolic disorders, cancer, and neurodegenerative diseases.
 
Professor Patrick Tan from Duke-NUS emphasized the importance of this discovery, stating: “Regulating our internal clock goes beyond curing jet lag - it’s about improving sleep quality, metabolism, and overall health. This important discovery could potentially open new doors for treatments that could transform how we manage these essential aspects of our daily lives.”
 
Conclusion: A Step Forward in Understanding the Body’s Clock
The discovery of how CK1δ regulates itself and influences our circadian rhythms represents a major leap forward in understanding the complex mechanisms that govern our body’s internal clock. By identifying the key sites on CK1δ’s tail that control its activity, scientists have unlocked new possibilities for treating a range of conditions, from jet lag and sleep disorders to more serious diseases like cancer.
 
This discovery underscores the importance of continued research into the molecular processes that regulate our health. The implications are far-reaching, with the potential to improve not just how we sleep but how we live our daily lives. As scientists continue to explore how CK1δ is influenced by lifestyle factors and environmental changes, we can look forward to more innovative solutions for managing our circadian rhythms.
 
The study findings were published in the peer-reviewed journal: PNAS.
https://www.pnas.org/doi/10.1073/pnas.2415567121
 
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