Journal
CELL
Volume 145, Issue 3, Pages 357-370Publisher
CELL PRESS
DOI: 10.1016/j.cell.2011.04.002
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Funding
- NIH [R01NS03498, K99/R00NS061952]
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The speed of circadian clocks in animals is tightly linked to complex phosphorylation programs that drive daily cycles in the levels of PERIOD (PER) proteins. Using Drosophila, we identify a time-delay circuit based on hierarchical phosphorylation that controls the daily downswing in PER abundance. Phosphorylation by the NEMO/NLK kinase at the per-short domain on PER stimulates phosphorylation by DOUBLETIME (DBT/CK1 delta/epsilon) at several nearby sites. This multisite phosphorylation operates in a spatially oriented and graded manner to delay progressive phosphorylation by DBT at other more distal sites on PER, including those required for recognition by the F box protein SLIMB/beta-TrCP and proteasomal degradation. Highly phosphorylated PER has a more open structure, suggesting that progressive increases in global phosphorylation contribute to the timing mechanism by slowly increasing PER susceptibility to degradation. Our findings identify NEMO as a clock kinase and demonstrate that long-range interactions between functionally distinct phospho-clusters collaborate to set clock speed.
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