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Molecular switch keeps the circadian clock running on time

Circadian rhythms help everything from plants to humans coordinate with the daily light-dark cycle, but how this natural clock keeps accurate time, or why it goes awry in people with sleep disorders, is still under investigation. New findings, published in Molecular Cell, suggest that a molecular switch balances the activity of two key proteins that keep the central timepiece of the clock--the daily accumulation and degradation of the PER2 protein--on schedule.

Abnormalities in this molecular switch may account for the symptoms of familial advanced sleep phase disorder (FASP)--a disorder that causes people to wake up and go to bed much earlier than normal due to abnormalities in the daily rhythmic fluctuations in PER2 levels--paving the way for new treatment strategies for a range of circadian clock-related conditions in humans.

"The balance between the two proteins--CK1 (casein kinase 1) and an unidentified priming kinase--can be regulated by drugs that affect circadian rhythms. Drugs to inhibit CK1 already exist; but this provides impetus to find drugs that inhibit the second, priming kinase," says senior study author David Virshup of Duke-NUS Graduate Medical School. "Our study also provides a mathematical model that predicts the behavior of the clock under different circumstances, so we have a good idea of when each drug will have an optimal effect to fight the effects of jet lag and shift work."

The abundance of PER2 rises and falls in a circadian pattern to control the sleep-wake cycle and other rhythmic behaviors. The degradation of this protein is triggered by a biochemical reaction called phosphorylation, a process in which enzymes called kinases add a phosphate group to PER2. However, there are multiple phosphorylation sites on PER2, and it has not been clear how they interact to control the clock's timing.

Virshup and Daniel Forger of the University of Michigan noticed that PER2 did not degrade exponentially, as previously thought, but rather degraded in three stages: an initial rapid decay, followed by a plateau-like slow decay, and then a more rapid decay at the end. Based on this finding, they developed a mathematical model of the circadian clock. This model predicted that the initial and final stages of rapid decay are caused by phosphorylation at the β-TrCP binding site by CK1. On the other hand, the second stage of plateau-like decay is driven by phosphorylation at the FASP site, first by an unknown priming kinase and then by CK1.

Experimental data confirmed the model's prediction: the "phosphoswitch" between the β-TrCP and FASP binding sites regulates PER2 stability in an opposing manner, affecting PER2's rate of degradation. This new insight provides a molecular explanation for the symptoms of FASP patients. Previous research has shown that this disorder is caused by a PER2 mutation that prevents phosphorylation by an unknown priming kinase at the FASP site.

The new findings mean that this mutation would cause less PER2 to enter the second slow stage of decay, resulting in more rapid degradation of this protein and an acceleration of the circadian clock. The phosphoswitch is also sensitive to temperature, and this explains how the circadian clock compensates, and sometimes overcompensates, for shifts in temperature

Virshup says future research should focus on using the new math model to predict the clock's response to drugs that modify rhythms. For example, the model predicts that CK1 inhibitors would block phosphorylation at both the β-TrCP and FASP binding sites, preventing the degradation of PER2 and slowing down the circadian clock. On the other hand, drugs that inhibit the priming kinase would only block phosphorylation at the FASP site, leading to faster PER2 degradation and an acceleration of the circadian rhythm. Thus, CK1 inhibitors might be an appropriate treatment strategy for FASP patients, whereas priming kinase inhibitors might treat the opposite problem: delayed-phase sleep syndrome.

"The identification of the priming kinase and the further development of CK1 inhibitors could prove key to treating sleep disorders," Virshup says. "Ultimately, this research could lead to the development of novel drugs that would broaden the current treatment options of melatonin, light, and behavioral therapy, which do not always effectively treat symptoms in patients."

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