Jet lag cure on the horizon? Tiny protein tail could hold the answer

SINGAPORE — Scientists have uncovered a crucial mechanism that regulates our body’s internal clock, and it all comes down to a small section at the end of a protein. This discovery could not only change our understanding of circadian rhythms but might also pave the way for new treatments for sleep disorders, jet lag, and even certain types of cancer.

At the heart of this breakthrough is a protein called Casein Kinase 1 delta (CK1δ), which acts as a pacemaker for our biological clock. This internal timekeeper governs our 24-hour cycles, influencing when we feel sleepy, hungry, or alert. Researchers from Duke-NUS Medical School and the University of California, Santa Cruz, have identified that the key to regulating this clock lies in the tail end of CK1δ.

The study, published in the Proceedings of the National Academy of Sciences, focused on two forms of CK1δ, known as δ1 and δ2, which differ by just 16 amino acids at their tail end. Despite this seemingly minor variation, these two forms have significantly different impacts on our circadian rhythms. The researchers discovered that the δ1 form tends to inhibit its own activity more than the δ2 form, thanks to a process called phosphorylation – the addition of phosphate groups to specific sites on the protein.

Using advanced spectroscopy and spectrometry techniques, the team zeroed in on three specific sites on the δ1 tail that are crucial for controlling the protein’s activity. When these sites are tagged with phosphate groups, CK1δ becomes less active, resulting in a weaker influence on our circadian rhythms.

“Our findings pinpoint to 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,” explains corresponding author Professor Carrie Partch, a biochemist and Howard Hughes Medical Institute Investigator from the University of California, Santa Cruz, in a statement. “Using high-resolution analysis, we were able to pinpoint the exact sites involved—and that’s really exciting.”

This self-regulation mechanism is vital for maintaining a balanced CK1δ activity, which in turn helps keep our internal clock running smoothly. When the researchers altered these phosphorylation sites, they observed significant changes in circadian rhythms in living cells, with the biological clock running about three hours faster than normal.

The implications of this research extend far beyond understanding why some people are early birds, and others are night owls. CK1δ is involved in several critical biological processes, including cell division and cancer development. By unraveling how this protein’s activity is regulated, scientists may open new avenues for treating not just circadian rhythm disorders but also a range of other conditions.

“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,” says co-corresponding author Professor David Virshup, director of the Cancer and Stem Cell Biology Programme at Duke-NUS, who first studied this protein over 30 years ago.

“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,” Virshup adds. “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.”

The research opens up exciting possibilities for personalized medicine. In the future, treatments for circadian rhythm disorders might be tailored based on an individual’s specific protein variants, offering more effective and targeted therapies.

Study authors plan to investigate how real-world factors like diet and environmental changes affect the phosphorylation sites on CK1δ. This could provide valuable insights into how these factors influence our circadian rhythms and potentially lead to practical solutions for managing disruptions to our body clocks.

As Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, notes: “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.”