Modelling the dual role of Per phosphorylation and its effect on the period and phase of the mammalian circadian clock.

Circadian clocks are regulated at the post-translational level by a variety of processes among which protein phosphorylation plays a prominent, although complex, role. Thus, the phosphorylation of different sites on the clock protein PER by casein kinase I (CKI) can lead to opposite effects on the stability of the protein and on the period of circadian oscillations. Here the authors extend a computational model previously proposed for the mammalian circadian clock by incorporating two distinct phosphorylations of PER by CKI. On the basis of experimental observations the authors consider that phosphorylation at one site (denoted here PER-P1) enhances the rate of degradation of the protein and decreases the period, while phosphorylation at another site (PER-P2) stabilises the protein, enhances the transcription of the Per gene, and increases the period. The model also incorporates an additional phosphorylation of PER by the Glycogen Synthase Kinase 3 (GSK3). The authors show that the extended model incorporating the antagonistic effects of PER phosphorylations by CKI can account for observations pertaining to (i) the decrease in period in the Tau mutant, because of an increase in phosphorylation by CKI leading to PER-P1, and (ii) the familial advanced sleep phase syndrome (FASPS) in which the period is shortened and the phase of the oscillations is advanced when the rate of phosphorylation leading to PER-P2 is decreased. The model further accounts for the increase in period observed in the presence of CKI inhibitors that decrease the rate of phosphorylation leading to both PER-P1 and PER-P2. A similar increase in period results from inhibition of GSK3. [Includes supplementary material].