Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime

Hyuk Wan Ko, Jin Jiang and Isaac Edery ()
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Hyuk Wan Ko: Graduate Program in Physiology and Neurobiology, Rutgers University, Center for Advanced Biotechnology and Medicine
Jin Jiang: University of Texas Southwestern Medical Center
Isaac Edery: Department of Molecular Biology and Biochemistry, Rutgers University, Center for Advanced Biotechnology and Medicine

Nature, 2002, vol. 420, issue 6916, 673-678

Abstract: Abstract Protein phosphorylation has a key role in modulating the stabilities of circadian clock proteins in a manner specific to the time of day1. A conserved feature of animal clocks is that Period (Per) proteins undergo daily rhythms in phosphorylation and levels2,3, events that are crucial for normal clock progression4,5,6,7. Casein kinase Iε (CKIε) has a prominent role in regulating the phosphorylation and abundance of Per proteins in animals8. This was first shown in Drosophila with the characterization of Doubletime (Dbt), a homologue of vertebrate casein kinase Iε4,6. However, it is not clear how Dbt regulates the levels of Per. Here we show, using a cell culture system, that Dbt promotes the progressive phosphorylation of Per, leading to the rapid degradation of hyperphosphorylated isoforms by the ubiquitin–proteasome pathway. Slimb, an F-box/WD40-repeat protein functioning in the ubiquitin–proteasome pathway9,10 interacts preferentially with phosphorylated Per and stimulates its degradation. Overexpression of slimb or expression in clock cells of a dominant-negative version of slimb disrupts normal rhythmic activity in flies. Our findings suggest that hyperphosphorylated Per is targeted to the proteasome by interactions with Slimb.

Date: 2002
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DOI: 10.1038/nature01272

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