期刊
GENES & DEVELOPMENT
卷 22, 期 13, 页码 1758-1772出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1682708
关键词
circadian rhythms; Drosophila; PER; beta-TrCP/SLIMB; CK1 epsilon/DBT; F-box protein; phosphorylation
资金
- NINDS NIH HHS [R01 NS034958, NS061952, F32 NS049862, NS049862, K99 NS061952, R00 NS061952] Funding Source: Medline
- PHS HHS [34958] Funding Source: Medline
A common feature of animal circadian clocks is the progressive phosphorylation of PERIOD ( PER) proteins, which is highly dependent on casein kinase I delta/epsilon (CKI delta/epsilon; termed DOUBLETIME [DBT] in Drosophila) and ultimately leads to the rapid degradation of hyperphosphorylated isoforms via a mechanism involving the F-box protein, beta-TrCP (SLIMB in Drosophila). Here we use the Drosophila melanogaster model system, and show that a key step in controlling the speed of the clock is phosphorylation of an N-terminal Ser (S47) by DBT, which collaborates with other nearby phosphorylated residues to generate a high-affinity atypical SLIMB-binding site on PER. DBT-dependent increases in the phospho-occupancy of S47 are temporally gated, dependent on the centrally located DBT docking site on PER and partially counterbalanced by protein phosphatase activity. We propose that the gradual DBT-mediated phosphorylation of a nonconsensus SLIMB-binding site establishes a temporal threshold for when in a daily cycle the majority of PER proteins are tagged for rapid degradation. Surprisingly, most of the hyperphosphorylation is unrelated to direct effects on PER stability. We also use mass spectrometry to map phosphorylation sites on PER, leading to the identification of a number of phospho-clusters that explain several of the classic per mutants.
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