Sep. 13, 1999 Researchers at the University of Pennsylvania Medical Center have solved the molecular intricacies of how a fruit fly controls the synchronization of its internal clock to cycles of light and dark. Life forms -- bacteria to humans -- rely on similar mechanisms to regulate their circadian cycles, or daily rhythms. As such, this research has far-reaching implications for understanding human sleep-wake cycles, metabolic rhythms, and other physiological functions that phase daily.
These clocks are genetically driven, relying on the waxing and waning of proteins whose levels control their own synthesis. Three years ago, the Penn team found that the cycling of these "clock" proteins -- specifically their degradation -- was controlled by exposure to light. Now, they explain how that degradation might occur at the molecular level. They report their findings in this week's issue of Science.
"We're finding out everyday that more and more in the human system might be controlled by our internal molecular clock, everything from our thresholds for pain, blood pressure, and basal body temperatures to hormone cycles," says senior author Amita Sehgal, PhD, associate professor of neuroscience and a Howard Hughes Medical Institute assistant investigator.
In previous work, Sehgal and her team found that the fruit fly clock is controlled by the cycling of two proteins called TIM and PER. Their amounts rise during the day, forming a two-protein complex that signals to the nucleus to turn off the timeless and period genes, which encode TIM and PER, respectively. The paired proteins disintegrate when exposed to light, completing the cycle. Specifically, light destroys TIM, after which PER lingers for a short while before also getting broken down, and the cycle starts anew. But, says Sehgal, "The question remained: How exactly was TIM broken down?"
Using several assays on fly brain tissue, the team found that the proteosome, a cellular structure made from several proteins, plays a key role in TIM's degradation. (The proteosome has been implicated in the breakdown of proteins important in many cellular processes.)
Sehgal surmises that the timeline for the breakdown goes like this. Light penetrates the brain mainly via the eyes, making its way to "clock" cells in the brain. "Within 20 minutes of light exposure phosphates are added to the TIM protein in a process called phosphorylation," notes Sehgal. "This is the first step in the breakdown." Ubiquitins, 76-amino-acid-long polypeptides, are then added to the TIM protein. Ubiquitin is essentially a molecular tag that signals the proteosome to degrade the TIM protein.
The National Science Foundation and the National Institutes of Health funded this research.
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