title: NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed.
abstract: 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/CK1δ/ɛ) 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/β-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.
authors.affiliation: Department of Molecular Biology and Biochemistry, Rutgers University, Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854, USA.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Chiu
authors.forename: Hyuk Wan
authors.initials: HW
authors.lastname: Ko
authors.forename: Isaac
authors.initials: I
authors.lastname: Edery
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D048149:Casein Kinase 1 epsilon / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D057906:Circadian Clocks; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D056950:Period Circadian Proteins / Q000378:metabolism*; D010766:Phosphorylation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; C113519:dco protein, Drosophila; C110233:slmb protein, Drosophila; D044767:Ubiquitin-Protein Ligases; D048149:Casein Kinase 1 epsilon; D020928:Mitogen-Activated Protein Kinases; C110707:nmo protein, Drosophila