Key molecular mechanism disrupting human biological clocks found

New Delhi: Scientists studying molecular mechanisms of our biological clocks have identified a key event that control the clock timing, by studying disrupted molecular interactions in people with an inherited sleep disorder called Familial Advanced Sleep Phase Syndrome (FASP).

It is known that molecular clocks in our cells synchronise our bodies with the cycle of night and day, cue us for sleep and waking, and drive daily cycles in virtually every aspect of our physiology.

20 years ago, a genetic mutation was found to cause the FASP syndrome by shortening the timing of the clock, making people extreme "morning larks", because their internal clocks operated on a 20-hour cycle instead of being in sync with the planet's 24-hour cycle.

"It's like having permanent jet lag, because their internal clock never gets caught up with the daylength," said corresponding author Carrie Partch, professor of chemistry and biochemistry at University of California Santa Cruz (UCSC), US.

"We knew (the FASP mutation) had a huge effect, but we didn't know how or why," said Partch.

The researchers have published their findings in the journal Molecular Cell.

The study showed how the FASP mutation, affecting a core clock protein called Period by changing a single amino acid in its structure, disrupts Period's interactions with a kinase enzyme (casein kinase 1). This destabilises the Period protein, thereby shortening an important step in the clock cycle.

The researchers explained that the kinase enzyme regulates Period through phosphorylation, or by attaching phosphate groups, and there are two different parts of the protein where it can do this.

While phosphorylation of the "degron" region tags Period for degradation, phosphorylation of the FASP region stabilises it.

The FASP mutation tilts the balance between degradation and stabilisation of Period, which determines the length of the clock cycle, towards degradation and shortening of the cycle.

"There's about a four-hour shortening of the clock when you have this FASP mutation," Philpott said.

The study importantly found that the phosphorylated FASP region inhibited kinase activity, which enabled Period to effectively regulate its own regulator, slowing the phosphorylation of the degron region and lengthening the cycle.

"We need this pause button to slow down what would otherwise be very fast biochemistry," Partch said.

The researchers further showed that the inhibition resulted from binding of the phosphorylated FASP region to a particular site on the kinase, which could be a potential drug target.

"We can start thinking about this as a tunable system," Philpott said. "We've identified regions on the kinase that are potentially targetable to tune its activity for therapeutic applications." Partch noted that most drugs that target kinases work by blocking the active site of the enzyme act like a "hammer" turning off the kinase activity.

"But with the discovery of new pockets unique to this kinase, we can target those to modulate its activity in a more controlled way," she said.

This, the researchers said, could help not only people with Familial Advanced Sleep Phase Syndrome, but also people whose sleep cycles are disrupted by shift work, jet lag, and other challenges of the modern world.