Abstract
Casein kinase 1 epsilon (CK1 epsilon) is an essential component of the circadian clock in mammals and Drosophila. The phosphorylation of Period (Per) proteins by CK1 epsilon is believed to be implicated in their subcellular localization and degradation, but the precise mechanism by which CK1 epsilon affects Per proteins has not been determined. In this study, three putative CK1 epsilon phosphorylation motif clusters in mouse Per1 (mPer1) were identified, and the phosphorylation status of serine and threonine residues in these clusters was examined. Phosphorylation of residues within a region defined by amino acids 653-663 and in particular of Ser-661 and Ser-663, was identified as responsible for the nuclear translocation of mPer1. Furthermore, phosphorylation of these residues may influence the nuclear translocation of a clock protein complex containing mPer1. These findings indicate that mPer1 phosphorylation is a critical aspect of the circadian clock mechanism.
Highlights
The metabolism and behavior of organisms are influenced by endogenous circadian rhythms
To clarify the function of CK1⑀ in the circadian clock mechanism, we identified mPer sites phosphorylated by CK1⑀ by performing in vitro kinase assays using a series of GST-mouse Per1 (mPer1) fragments as substrates for rCK1⑀ (Fig. 1A)
The region of mPer1 that is targeted by rCK1⑀ is located between the PAS domain and the putative nuclear localization signal (NLS) (Fig. 1B)
Summary
Cryptochrome protein; dPer, Drosophila Period protein; Dbt, Drosophila Double-time protein; aa, amino acid(s); FASPS, familial advanced sleep-phase syndrome; NLS, nuclear localization signal; GST, glutathione S-transferase; HA, hemagglutinin; CFP, cyan fluorescent protein; LMB, Leptomycin B; NES, nuclear export signal
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