title: Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime.
abstract: 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 Iepsilon (CKIepsilon) 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 Iepsilon. 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.
authors.affiliation: Graduate Program in Physiology and Neurobiology, Rutgers University, Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, New Jersey 08854, USA.
authors.forename: Hyuk Wan
authors.initials: HW
authors.lastname: Ko
authors.forename: Jin
authors.initials: J
authors.lastname: Jiang
authors.forename: Isaac
authors.initials: I
authors.lastname: Edery
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001683:Biological Clocks; D048149:Casein Kinase 1 epsilon; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002940:Circadian Rhythm; D003546:Cysteine Endopeptidases / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D056950:Period Circadian Proteins; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; D020033:Protein Isoforms; C113519:dco protein, Drosophila; C110233:slmb protein, Drosophila; C096445:tim protein, Drosophila; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D048149:Casein Kinase 1 epsilon; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex