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National Institute of Environmental Health Sciences

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Publication Detail

Title: Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability.

Authors: Shanware, Naval P; Hutchinson, John A; Kim, Sang Hwa; Zhan, Lihong; Bowler, Michael J; Tibbetts, Randal S

Published In J Biol Chem, (2011 Apr 08)

Abstract: The mammalian circadian clock component PERIOD2 (PER2) plays a critical role in circadian rhythm entrainment. Recently, a missense mutation at a putative phosphorylation site in hPER2, Ser-662, was identified in patients that suffer from familial advanced sleep phase syndrome (FASPS). Patients with FASPS display abnormal sleep-wake patterns characterized by a lifelong pattern of sleep onset in the early evening and offset in the early morning. Although the phosphorylation of PER2 is strongly implied from functional studies, it has not been possible to study the site-specific phosphorylation of PER2 on Ser-662, and the biochemical functions of this residue are unclear. Here, we used phospho-specific antibodies to show that PER2 is phosphorylated on Ser-662 and flanking casein kinase (CK) sites in vivo. The phosphorylation of PER2 was carried out by the combined activities of casein kinase 1δ (CK1 δ) and casein kinase 1ε (CK1ε) and was antagonized by protein phosphatase 1. PER2 phosphorylation was rapidly induced in response to circadian entrainment of mammalian cell lines and occurred in both cytosolic and nuclear compartments. Importantly, we found that the pool of Ser-662-phosphorylated PER2 proteins was more stable than the pool of total PER2 molecules, implying that the FASPS phosphorylation cluster antagonizes PER2 degradation. Consistent with this idea, a Ser-662→Ala mutation that abrogated PER2 phosphorylation significantly reduced its half-life, whereas a phosphomimetic Ser-662→Asp substitution led to an elevation in half-life. Our combined findings provide new insights into PER2 regulation and the biochemical basis of FASPS.

PubMed ID: 21324900 Exiting the NIEHS site

MeSH Terms: Animals; Casein Kinase I/metabolism*; Cell Line; Circadian Rhythm/genetics; Humans; Immunoblotting; Mice; NIH 3T3 Cells; Period Circadian Proteins/metabolism*; Phosphoprotein Phosphatases/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; Sleep Disorders, Circadian Rhythm/metabolism*

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