The F-box protein slimb controls the levels of clock proteins period and timeless.
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.
Grima
Brigitte
B
Institut de Neurobiologie Alfred Fessard (NGI, CNRS UPR 2216), Centre National de la Recherche Scientifique, av. de la terrasse, 91198 Gif-sur-Yvette, France.
Lamouroux
Annie
A
Chélot
Elisabeth
E
Papin
Christian
C
Limbourg-Bouchon
Bernadette
B
Rouyer
François
F
D020816:Amino Acid Motifs; D000818:Animals; D001683:Biological Clocks; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm; D003624:Darkness; D004330:Drosophila / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D019476:Insect Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008027:Light; D008970:Molecular Weight; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D009687:Nuclear Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; D012333:RNA, Messenger; C110233:slmb protein, Drosophila; C096445:tim protein, Drosophila; D044767:Ubiquitin-Protein Ligases