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Decoupling PER phosphorylation, stability and rhythmic expression from circadian clock function by abolishing PER-CK1

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Area of Science:

  • Chronobiology
  • Molecular biology
  • Mammalian circadian rhythms

Background:

  • Mammalian circadian clocks rely on robust rhythms of PERIOD (PER) protein abundance and phosphorylation.
  • PER protein stability is considered a key factor in determining circadian period length.
  • Casein kinase 1 (CK1) forms stable complexes with PER proteins in mammals.

Purpose of the Study:

  • To identify specific PER residues crucial for the PER-CK1 interaction.
  • To investigate the functional consequences of disrupting the PER-CK1 interaction in cellular and in vivo models.
  • To elucidate the role of PER-CK1 interaction in regulating circadian feedback mechanisms and clock output.

Main Methods:

  • Site-directed mutagenesis to identify PER residues essential for CK1 binding.
  • Cell-based assays to assess PER phosphorylation and stability.
  • In vivo studies using mutant mice to analyze locomotor activity and molecular rhythms.
  • Western blotting and immunoprecipitation to examine protein interactions and phosphorylation states.

Main Results:

  • Mutating PER residues essential for PER-CK1 interaction abolished PER phosphorylation and led to CLOCK hyperphosphorylation.
  • This mutation resulted in PER stabilization, arrhythmic PER abundance, and impaired negative feedback.
  • Mutant mice displayed robust short-period locomotor activity and physiological rhythms but low-amplitude molecular rhythms.
  • PER-CK1 interaction was found to have opposing roles in regulating CLOCK-BMAL1 activity.

Conclusions:

  • The circadian clock can maintain robust rhythms independently of PER phosphorylation and abundance rhythms via an alternative PER-CRY-dependent feedback loop.
  • Circadian period length can be uncoupled from PER protein stability.
  • PER acts as a scaffold for CK1 within the circadian feedback mechanism.