Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch
Shusaku Masuda, Rajesh Narasimamurthy, Hikari Yoshitane, Jae Kyoung Kim, Yoshitaka Fukada, David M. Virshup
Abstract
Significance The speed of the circadian clock is regulated by phosphorylation-regulated degradation of the PER protein. However, this model has recently been challenged by genetic studies in mice and fungi. Here, we provide definitive genetic and biochemical evidence that strongly supports the importance of the phosphoswitch-regulated proteolysis of PER2 in regulating the clock. We generated two independent mouse lines with a point mutation in a casein kinase 1-dependent phosphodegron in PER2. These mice have longer circadian rhythms, increased accumulation of circadian proteins, and perturbed temperature compensation. The findings strongly support the phosphoswitch model of regulated PER2 degradation as a central mechanism controlling the speed of the circadian clock.