NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed

Cell. 2011 Apr 29;145(3):357-70. doi: 10.1016/j.cell.2011.04.002.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Casein Kinase Iepsilon / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Circadian Clocks*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism
  • Drosophila melanogaster / physiology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Period Circadian Proteins / metabolism*
  • Phosphorylation
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Cell Cycle Proteins
  • Drosophila Proteins
  • PER protein, Drosophila
  • Period Circadian Proteins
  • dco protein, Drosophila
  • slmb protein, Drosophila
  • Ubiquitin-Protein Ligases
  • Casein Kinase Iepsilon
  • Mitogen-Activated Protein Kinases
  • nmo protein, Drosophila