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The switch involves a section of the CK1 protein called the activation loop. One conformation of this loop favors binding of CK1 to the "degron" region of PER, where phosphorylation leads to the protein's degradation. The clock-changing mutations in CK1 cause it to favor this degron-binding conformation.
The other conformation favors binding to a site on the PER protein known as the FASP region, because mutations in this region lead to an inherited sleep disorder called Familial Advanced Sleep Phase Syndrome. The stabilization of PER can be disrupted by either the FASP mutations, which interfere with the binding of CK1 to this region, or by the mutations in CK1 that favor the alternate conformation of the activation loop.
The new findings also suggest why binding of CK1 to the FASP region stabilizes PER. With phosphorylation of the FASP region, that region then acts to bind and inhibit CK1, preventing it from adopting the other conformation and phosphorylating the degron region.
"It binds and locks the kinase down, so it's like a pause button that prevents the PERIOD protein from being degraded too soon," Partch said. "This stabilizing region builds a delay into the clock to make it align with Earth's 24-hour day."
Partch noted that it is important to understand how these clock proteins regulate our circadian rhythms, because those rhythms affect not only the sleep cycle but almost every aspect of our physiology. Understanding these molecular mechanisms may enable scientists to develop therapies for intervening in the clock to alleviate disruptions, whether they are caused by inherited conditions or by shift work or jet lag.
"There might be ways to mitigate some of those effects," she said.
CK1 is also interesting because it seems to be the most ancient component of biological clocks. The whole feedback loop involving CK1, PERIOD, and other core clock proteins is found in all animals from insects to humans. CK1, however, is also found in every other organism with eukaryotic (nonbacterial) cells, including single-celled green algae in which it has been implicated in circadian rhythms.
"Our results provide a mechanistic foundation to understand the essentially universal role of CK1 as a regulator of eukaryotic circadian clocks," Partch said. Source:
University of California - Santa Cruz Journal reference:
Philpott, J.M., et al. (2020) Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch. eLife . doi.org/10.7554/eLife.52343.
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