A Period2 Phosphoswitch Regulates and Temperature Compensates Circadian Period

• Published in: Molecular cell 2015-10, Vol.60 (1), p.77-88
• Main Authors: Zhou, Min, Kim, Jae Kyoung, Eng, Gracie Wee Ling, Forger, Daniel B., Virshup, David M.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Circadian Rhythm; Mice; Models, Biological; NIH 3T3 Cells; Period Circadian Proteins - chemistry; Period Circadian Proteins - metabolism; Phosphorylation; Protein Stability; Proteolysis; Temperature
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.08.022

Period (PER) protein phosphorylation is a critical regulator of circadian period, yet an integrated understanding of the role and interaction between phosphorylation sites that can both increase and decrease PER2 stability remains elusive. Here, we propose a phosphoswitch model, where two competing phosphorylation sites determine whether PER2 has a fast or slow degradation rate. This mathematical model accurately reproduces the three-stage degradation kinetics of endogenous PER2. We predict and demonstrate that the phosphoswitch is intrinsically temperature sensitive, slowing down PER2 degradation as a result of faster reactions at higher temperatures. The phosphoswitch provides a biochemical mechanism for circadian temperature compensation of circadian period. This phosphoswitch additionally explains the phenotype of Familial Advanced Sleep Phase (FASP) and CK1εtau genetic circadian rhythm disorders, metabolic control of PER2 stability, and how drugs that inhibit CK1 alter period. The phosphoswitch provides a general mechanism to integrate diverse stimuli to regulate circadian period. [Display omitted] •PER2 degradation follows three-stage kinetics, consistent with a phosphoswitch model•Inclusion of a phosphoswitch suggests a temperature compensation mechanism•This phosphoswitch integrates diverse environmental stimuli to tune PER2 stability•The phosphoswitch is a design feature of the clock It’s been long known that circadian clocks compensate for changes in temperature, but the molecular mechanism has been elusive. Zhou, Kim, and coworkers describe a dual-kinase, multisite phosphoswitch that regulates stability of the PERIOD protein and provides for environmental and metabolic control of the clock, including temperature compensation.