Ending jet lag: Scientists discover secret to regulating our body clock

Good news! Now we need hypersonic planes to travel faster!

"Scientists have discovered a revolutionary way to put an end to jet lag by uncovering the secret at the tail end of Casein Kinase 1 delta (CK1δ), a protein that regulates our body clock. This breakthrough, achieved by researchers ... offers a new approach to adjusting our circadian rhythms, the natural 24-hour cycles that influence sleep-wake patterns and overall daily functions. ...

Using advanced spectroscopy and spectrometry techniques to zoom in on the tails, the researchers found that how the proteins are tagged is determined by their distinct tail sequences. ..."

"... This discovery highlights how a small part of CK1δ can greatly influence its overall activity. This self-regulation is vital for keeping CK1δ activity balanced, which, in turn, helps regulate our circadian rhythms.

The study also addressed the wider 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’s activity is regulated, scientists could open new avenues for treating not just circadian rhythm disorders but also a range of conditions. ..."

From the significance and abstract:

"Subtle control of kinase activity is critical to physiologic modulation of multiple physiological processes including circadian rhythms. Casein kinase 1δ (CK1δ) and the closely related Casein kinase 1 epsilon (CK1ε) regulate circadian rhythms by phosphorylation of PERIOD2 (PER2), but how kinase activity itself is controlled is not clear. Building on the prior observation that two splice isoforms of CK1δ have opposite effects on the circadian period, we show that the difference maps to three phosphorylation sites specific to δ1 in the variably spliced region [extreme C termini (XCT)] that cause feedback inhibition of the kinase domain. More broadly, the data suggest a general model where CK1 activity on diverse substrates can be controlled by signaling pathways that alter tail phosphorylation.

Abstract

Casein kinase 1δ (CK1δ) controls essential biological processes including circadian rhythms and wingless-related integration site (Wnt) signaling, but how its activity is regulated is not well understood. CK1δ is inhibited by autophosphorylation of its intrinsically disordered C-terminal tail. Two CK1 splice variants, δ1 and δ2, are known to have very different effects on circadian rhythms. These variants differ only in the last 16 residues of the tail, referred to as the extreme C termini (XCT), but with marked changes in potential phosphorylation sites. Here, we test whether the XCT of these variants have different effects in autoinhibition of the kinase. Using NMR and hydrogen/deuterium exchange mass spectrometry, we show that the δ1 XCT is preferentially phosphorylated by the kinase and the δ1 tail makes more extensive interactions across the kinase domain. Mutation of δ1-specific XCT phosphorylation sites increases kinase activity both in vitro and in cells and leads to changes in the circadian period, similar to what is reported in vivo. Mechanistically, loss of the phosphorylation sites in XCT disrupts tail interaction with the kinase domain. δ1 autoinhibition relies on conserved anion-binding sites around the CK1 active site, demonstrating a common mode of product inhibition of CK1δ. These findings demonstrate how a phosphorylation cycle controls the activity of this essential kinase."

Ending jet lag: Scientists discover secret to regulating our body clock

Scientists discover a secret to regulating our body clock, offering new approach to end jet lag (original news release) "A team of scientists in Singapore and the US uncovered how a protein that controls our biological clock modifies its own function, offering new ways for treating jet lag and seasonal adjustments"

Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein kinase 1 (open access)

Fig. 1 CK1δ isoforms change kinase activity in vitro and regulation of XCT phosphorylation in cells.

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.