Molecular Mechanisms Regulating Temperature Compensation of the Circadian Clock

Abstract

An approximately 24-h biological timekeeping mechanism called the circadian clock is present in virtually all light-sensitive organisms from cyanobacteria to humans. The clock system regulates our sleep-wake cycle, feeding-fasting, hormonal secretion, body temperature, and many other physiological functions. Signals from the master circadian oscillator entrain peripheral clocks using a variety of neural and hormonal signals. Even centrally controlled internal temperature fluctuations can entrain the peripheral circadian clocks. But, unlike other chemical reactions, the output of the clock system remains nearly constant with fluctuations in ambient temperature, a phenomenon known as temperature compensation. In this brief review, we focus on recent advances in our understanding of the posttranslational modifications, especially a phosphoswitch mechanism controlling the stability of PER2 and its implications for the regulation of temperature compensation.

Keywords: circadian clock; period2; phosphorylation; phosphoswitch; temperature compensation.

Figure 1

Regulation of PER2 phosphorylation, degradation, and its role in temperature compensation by the phosphoswitch mechanism. Lower temperature increases relative phosphorylation at the β-TrCP site of PER2, leading to faster degradation and shorter period. Higher temperature increases relative familial advanced sleep phase (FASP) site phosphorylation, enhancing PER2 stability and lengthening the period. The degradation pattern of PER2 at 30°C is largely exponential, while at 37°C, three-phase degradation is seen. This has important implications for temperature compensation (see text for details). Domain architectures are shown in colors. PAS1, PAS domain 1 (orange); PAS 2, PAS domain 2 (grey); CK1, Casein kinase 1-binding domain (green); CRY, Cry binding site (blue).