The F-box protein Slimb controls the levels of clock proteins Period and Timeless

• Published in: Nature (London) 2002-11, Vol.420 (6912), p.178-182
• Main Authors: Rouyer, François, Grima, Brigitte, Lamouroux, Annie, Chélot, Elisabeth, Papin, Christian, Limbourg-Bouchon, Bernadette
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Animals; Biochemistry. Physiology. Immunology; Biological and medical sciences; Biological Clocks; Cell Cycle Proteins; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Circadian Rhythm; Circadian rhythms; Darkness; Degradation; Drosophila; Drosophila - cytology; Drosophila - genetics; Drosophila - metabolism; Drosophila Proteins; Drosophila Proteins - chemistry; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Fluctuations; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Humanities and Social Sciences; Insect Proteins; Insect Proteins - chemistry; Insect Proteins - genetics; Insect Proteins - metabolism; Insecta; Insects; Invertebrates; letter; Life Sciences; Light; Molecular and cellular biology; Molecular genetics; Molecular Weight; Motor Activity; Motor Activity - physiology; multidisciplinary; Mutants; Mutation; Neurons; Neurons - metabolism; Neurons and Cognition; Nuclear Proteins; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Period Circadian Proteins; Phosphorylation; Physiology. Development; Protein Processing, Post-Translational; Proteins; RNA, Messenger; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Ubiquitin-Protein Ligases
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature01122

The Drosophila circadian clock is driven by daily fluctuations of the proteins Period and Timeless, which associate in a complex and negatively regulate the transcription of their own genes. Protein phosphorylation has a central role in this feedback loop, by controlling Per stability in both cytoplasmic and nuclear compartments as well as Per/Tim nuclear transfer. However, the pathways regulating degradation of phosphorylated Per and Tim are unknown. Here we show that the product of the slimb (slmb) gene-a member of the F-box/WD40 protein family of the ubiquitin ligase SCF complex that targets phosphorylated proteins for degradation-is an essential component of the Drosophila circadian clock. slmb mutants are behaviourally arrhythmic, and can be rescued by targeted expression of Slmb in the clock neurons. In constant darkness, highly phosphorylated forms of the Per and Tim proteins are constitutively present in the mutants, indicating that the control of their cyclic degradation is impaired. Because levels of Per and Tim oscillate in slmb mutants maintained in light:dark conditions, light- and clock-controlled degradation of Per and Tim do not rely on the same mechanisms.