Researchers from the University of California and Duke-NUS Medical School have figured out how to control the human body's internal clock. This regulator is located at the end of Casein Kinase 1 delta (CK1δ), a protein that sets the pace for circadian rhythm, or internal biological clock, which regulates sleep-wake cycles and other daily activities.
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 less able to fine-tune the body’s internal clocks. Image Credit: Jon Philpott, Rajesh Narasimamurthy, and David Virshup
Their findings, published in the journal PNAS, may lead to novel treatments for circadian rhythm conditions.
By attaching itself to other proteins that are part of the biological clock, CK1δ controls circadian rhythms and adjusts their timing. Besides changing other proteins, CK1δ can also be tagged, which will change its capacity to control the proteins the body uses to run its internal clock.
Just 16 amino acids, or building blocks, separate the two forms of CK1δ, referred to as isoforms δ1 and δ2, found near the end of the protein in a region known as the C-terminal tail.
CK1δ's functioning is greatly affected by these little variations. Although it was known that these proteins' capacity to control the body clock diminished when they were tagged, the precise mechanism behind this was unknown.
By using sophisticated spectroscopy and spectrometry techniques to focus on the tails, the researchers discovered that the unique tail sequences of the proteins dictate how they are tagged.
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 does not influence our circadian rhythms as effectively. Using high-resolution analysis, we were able to pinpoint the exact sites involved and that is really exciting.”
Carrie Partch, Professor and Study Corresponding Author, Department of Chemistry & Biochemistry, University of California
Carrie Partch is also a Howard Hughes Medical Institute investigator.
Professor David Virshup, the Director of the Cancer and Stem Cell Biology Programme at Duke-NUS and co-corresponding author of the study, reflected on his initial research on this protein over 30 years ago when examining its role in cell division.
With the technology we have available now, we were finally able to get to the bottom of a question that has gone 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 self-inhibition compared to δ2. This means that δ1 is more tightly regulated by its tail than δ2. When these sites are mutated or removed, δ1 becomes more active, which leads to changes in circadian rhythms. In contrast, δ2 does not have the same regulatory effect from its tail region.”
David Virshup, Professor and Study Co-Corresponding Author, Duke-NUS Medical School
This finding demonstrates how a tiny portion of CK1δ can significantly impact the protein's total function. This self-regulation is crucial for keeping CK1δ activity balanced, which, in turn, helps regulate circadian rhythms.
The research also discussed the broader ramifications of these findings. Beyond circadian rhythms, CK1δ is involved in various critical processes, including cell division, the onset of cancer, and a few neurological illnesses. Gaining more insight into the regulation of CK1δ activity could lead to novel treatment approaches for various illnesses, not just circadian rhythm problems.
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 for treatments that could transform how we manage these essential aspects of our daily lives.”
Patrick Tan, Professor and Senior Vice-Dean for Research, Duke-NUS Medical School
The impact of environmental changes and dietary modifications on the tagging sites on CK1δ will be examined in more detail by the researchers in their future research. This may show how these variables impact circadian rhythms and result in workable ways to deal with disturbances.
Duke-NUS is a global leader in medical education and biomedical research, producing innovations that transcend scientific curiosity for the benefit of the communities. Integrating scientific research and translational methodologies, the School enhances comprehension of common diseases and creates novel treatment strategies.
Source:
Journal reference:
Harold, R. L., et al. (2024) Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein kinase 1. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2415567121.