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1 Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, 10115 Berlin, Germany; 2 Institute for Theoretical Biology, Humboldt-University Berlin, 10115 Berlin, Germany; 3 Institute for Biology, Center of Biophysics and Bioinformatics, Humboldt-University Berlin, 10115 Berlin, Germany
PERIOD (PER) proteins are central components within the mammalian circadian oscillator, and are believed to form a negative feedback complex that inhibits their own transcription at a particular circadian phase. Phosphorylation of PER proteins regulates their stability as well as their subcellular localization. In a systematic screen, we have identified 21 phosphorylated residues of mPER2 including Ser 659, which is mutated in patients suffering from familial advanced sleep phase syndrome (FASPS). When expressing FASPS-mutated mPER2 in oscillating fibroblasts, we can phenocopy the short period and advanced phase of FASPS patients’ behavior. We show that phosphorylation at Ser 659 results in nuclear retention and stabilization of mPER2, whereas phosphorylation at other sites leads to mPER2 degradation. To conceptualize our findings, we use mathematical modeling and predict that differential PER phosphorylation events can result in opposite period phenotypes. Indeed, interference with specific aspects of mPER2 phosphorylation leads to either short or long periods in oscillating fibroblasts. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster as well as the doubletime mutants (dbtS and dbtL ) in Drosophila.
[Keywords: Circadian; phosphorylation; PER; FASPS]
Received June 13, 2006; revised version accepted July 31, 2006.
E-MAIL achim.kramer{at}charite.de; FAX 49-30-450-524942.
Supplemental material is available at http://www.genesdev.org.
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.397006.
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Genes & Dev. 2006 20: 2629-2633.
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