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

• Published in: Nature (London) 2002-12, Vol.420 (6916), p.673-678
• Main Authors: Edery, Isaac, Ko, Hyuk Wan, Jiang, Jin
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Biological Clocks; Casein Kinase Iepsilon; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Circadian Rhythm; Circadian rhythms; Cysteine Endopeptidases - metabolism; Drosophila; Drosophila melanogaster - cytology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila melanogaster - physiology; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Humanities and Social Sciences; Insect Proteins - genetics; Insect Proteins - metabolism; Insects; letter; Motor Activity; multidisciplinary; Multienzyme Complexes - metabolism; Mutation - genetics; Neurology; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Period Circadian Proteins; Phosphorylation; Proteasome Endopeptidase Complex; Protein Binding; Protein Isoforms - metabolism; Protein Kinases - genetics; Protein Kinases - metabolism; Proteins; RNA Interference; Science; Science (multidisciplinary); Substrate Specificity; Ubiquitin-Protein Ligases; Vertebrates
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature01272

Protein phosphorylation has a key role in modulating the stabilities of circadian clock proteins in a manner specific to the time of day. A conserved feature of animal clocks is that Period (Per) proteins undergo daily rhythms in phosphorylation and levels, events that are crucial for normal clock progression. Casein kinase I (CKI ) has a prominent role in regulating the phosphorylation and abundance of Per proteins in animals. This was first shown in Drosophila with the characterization of Doubletime (Dbt), a homologue of vertebrate casein kinase I . 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 pathway 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.