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October 27, 2003
Johns Hopkins researchers have uncovered a key step in the body's regulation of melatonin, a major sleep-related chemical in the brain.
In the advance online section of Nature Structural Biology, the research team reports finding the switch that causes destruction of the enzyme that makes melatonin -- no enzyme, no melatonin.
Melatonin levels are high at night and low during the day. Even at night, melatonin disappears after exposure to bright light, a response that likely contributes to its normal daily cycle, but plagues shift workers and jet setters by leading to sleeplessness. To help understand melatonin's light-induced disappearance, the Hopkins researchers turned to the enzyme that makes it, a protein called AANAT.
One way cells turn proteins like AANAT on and off is by modifying them, attaching or removing small bits, such as phosphate groups, to particular spots along the protein's backbone. For AANAT, the key spot turns out to be building block number 31, the researchers have found.
"We have discovered that addition and removal of the phosphate group at this position is the key step in regulating the enzyme's stability," says Philip Cole, M.D., Ph.D., professor and director of pharmacology and molecular sciences in Hopkins' Institute for Basic Biomedical Sciences. "When this phosphate group is present, the enzyme is stable."
To test the importance of the phosphate group to the enzyme's stability, research associate Weiping Zheng, Ph.D., developed a mimic of the key building block with the equivalent of a permanently affixed phosphate group.
Zheng inserted the mimic into the appropriate place in the enzyme, and research associate Zhongsen Zhang injected the altered enzyme into cells. The altered enzyme stayed intact in the cells much longer than the normal enzyme, whose phosphate group can easily be removed, the scientists report.
The researchers' next step is to determine how exposure to light accelerates removal of the phosphate and destruction of the enzyme, leading to a rapid drop off in melatonin. "Now we can fish for unknown players in the degradation of the enzyme and hopefully find the trigger than leads to its light-activated destruction," says Zheng.
They've already shown that the phosphate group on building block number 31 also improves the enzyme's ability to bind to a protein known as 14-3-3, further increasing the enzyme's stability and delaying its degradation.
Cole adds that the mimic Zheng developed will do far more than just ease study of melatonin's daily cycles. Literally thousands of important proteins are controlled by the addition or removal of phosphate groups, he says, offering thousands of opportunities to use the mimic to help understand cellular processes and their controls.
Funding for the study was provided by the National Institutes of Health and the Ellison Medical Foundation. Aspects of the work were carried out at the AB Mass Spectrometry/Proteomics Facility at the Johns Hopkins School of Medicine, which is funded by the U.S. National Center for Research Resources, the Johns Hopkins Fund for Medical Discovery and the Johns Hopkins Institute for Cell Engineering.
Authors on the study are Zheng, Zhang and Cole of The Johns Hopkins University School of Medicine, and Surajit Ganguly, David Klein and Joan Weller of the National Institutes of Health.
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