Researchers studying the molecular underpinnings of our biological clocks have made tremendous advancements in understanding how a specific event regulates the timing of these clocks. Scientists discovered disturbed molecular interactions that play a critical role in clock regulation by studying people with an inherited sleep disease known as Familial Advanced Sleep Phase Syndrome (FASP).A genetic mutation linked to FASP was discovered about 20 years ago. Individuals with this mutation exhibited severe “morning lark” behaviour as a result of their internal clocks functioning on a 20-hour cycle rather than the standard 24-hour cycle synchronised with the day-night cycle. Carrie Partch, a professor at the University of California Santa Cruz (UCSC) and the studys corresponding author, described this situation as “permanent jet lag” because their internal clocks never adjust to the real duration of the day.Although the FASP mutation had a significant impact, the underlying processes remained unknown. However, the results of the study have now been published in the journal Molecular Cell, offering light on how the FASP mutation impacts a crucial clock protein called Period.Image: PixabayAccording to the findings, the FASP mutation modifies the structure of the Period protein by modifying a single amino acid. This change affects the proteins interactions with casein kinase 1, a kinase enzyme that destabilises the Period. As a consequence, a critical step in the clock cycle is shortened. The kinase enzyme controls the Period by phosphorylating it (adding phosphate groups), according to the researchers. Phosphorylation can occur in two different locations of the protein. The Period is marked for degradation by phosphorylation of the “degron” region, whereas the FASP area is stabilised by phosphorylation of the FASP region.The FASP mutation alters the Periods precise balance of degradation and stabilisation, resulting in a shorter clock cycle. The length of the cycle is reduced by four hours as a result of this mutation. The findings show that the phosphorylated FASP region blocks kinase activity, allowing Period to regulate its own regulator. The clock cycle is extended as phosphorylation of the degron region slows.Partch claims that this mechanism functions as a “pause button” to control otherwise fast metabolic processes. The inhibition occurs when the phosphorylated FASP region binds to a specific spot on the kinase, presenting a possible target for therapeutic interventions, according to scientists.The researchers hope to construct a tunable system by identifying areas on the kinase that may be targeted to adjust its activity. Unlike previous kinase-targeting medications, which block the enzymes active site like a “hammer,” these new results allow for more precise control of the enzymes activity by targeting specific pockets on the kinase. This study holds hope not only for those with Familial Advanced Sleep Phase Syndrome but also for people who have interrupted sleep cycles due to shift work, jet lag, and other modern-day issues.
