第1242回生物科学セミナー
CK1δ/ε protein kinases prime the PER2 circadian phosphoswitch
Prof. David M Virshup（Duke-NUS Medical School, Singapore）
2018年10月31日(水) 14:00-15:30 理学部3号館 326号室
Multisite phosphorylation of the PER2 protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by Casein kinase 1 (CK1), an essential clock component that is conserved from algae to humans. These subsequent phosphorylations stabilize PER2, delay its degradation and lengthen the period of the circadian clock. We performed a comprehensive biochemical and biophysical analysis of mouse PER2 (mPER2) priming phosphorylation and found, surprisingly, that CK1δ/ε are indeed the priming kinases. In collaboration with JM Fustin (Kyoto) we found that CK1ε and a newly characterized CK1δ2 splice variant more efficiently prime mPER2 for downstream phosphorylation in cells than the well-studied splice variant CK1δ1. While CK1 phosphorylation of PER2 was previously shown to be robust to changes in the cellular environment, our phosphoswitch mathematical model of circadian rhythms shows that the CK1 carboxyl terminal tail can allow the period of the clock to be sensitive to cellular signaling. These studies implicate the extreme carboxyl terminus of CK1 as a key regulator of circadian timing.
