Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5

Carrie L Partch1, Katherine F Shields1, Carol L Thompson1

  • 1Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599.

Insights

Protein phosphatase 5 (PP5) regulates casein kinase I epsilon (CKIε) activity, a key component of the mammalian circadian clock. Cryptochrome modulates this interaction, impacting circadian rhythmicity.

Area of Science:

  • Chronobiology
  • Molecular Biology
  • Biochemistry

Background:

  • Mammalian circadian rhythms rely on molecular oscillators driven by posttranslational modification of clock proteins.
  • The major clock kinase, casein kinase I epsilon (CKIε), has its activity regulated by autophosphorylation.

Purpose of the Study:

  • To investigate the role of protein phosphatase 5 (PP5) in regulating CKIε activity.
  • To determine how cryptochrome influences clock protein phosphorylation via PP5 and CKIε.

Main Methods:

  • Assessed the effect of PP5 on CKIε kinase activity.
  • Investigated cryptochrome's modulation of PP5's effect on CKIε.
  • Examined PP5 and CKIε expression in the suprachiasmatic nuclei and peripheral tissues.
  • Utilized dominant-negative PP5 mutants and PP5 down-regulation in cell culture models.

Main Results:

  • Protein phosphatase 5 (PP5) was identified as a regulator of casein kinase I epsilon (CKIε) activity.
  • Cryptochrome modulates CKIε activity by affecting the interaction between PP5 and CKIε.
  • PP5 down-regulation significantly reduced the amplitude of circadian cycling in human fibroblasts.

Conclusions:

  • PP5, CKIε, and cryptochrome are key components in the dynamic regulation of the mammalian circadian clock.
  • This study elucidates a novel regulatory pathway involving PP5 in circadian rhythmicity.

Related Concept Videos

Circadian Rhythms and Gene Regulation02:19

Circadian Rhythms and Gene Regulation

The biological clock is involved in many aspects of regulating complex physiology in all animals. It was in 1935 when German zoologists, Hans Kalmus and Erwin Bünning, discovered the existence of circadian rhythm in Drosophila melanogaster. However, the internal molecular mechanisms behind the circadian clock remained a mystery until 1984, when Jeffrey C. Hall, Michael Rosbash, and Michael W. Young discovered the expression of the Per gene oscillating over a 24-hour cycle. In subsequent years,...
Circadian Rhythms and Gene Regulation02:19

Circadian Rhythms and Gene Regulation

The biological clock is involved in many aspects of regulating complex physiology in all animals. It was in 1935 when German zoologists, Hans Kalmus and Erwin Bünning, discovered the existence of circadian rhythm in Drosophila melanogaster. However, the internal molecular mechanisms behind the circadian clock remained a mystery until 1984, when Jeffrey C. Hall, Michael Rosbash, and Michael W. Young discovered the expression of the Per gene oscillating over a 24-hour cycle. In subsequent years,...
Positive Regulator Molecules02:39

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
Positive Regulator Molecules01:45

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...