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The phospho-occupancy of an atypical SLIMB-binding site on PERIOD that is phosphorylated by DOUBLETIME controls the pace of the clock

¹ Rutgers University, Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, USA; ² Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, 10115 Berlin, Germany; ³ Department of Molecular Biology and Biochemistry, Rutgers University, Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, USA

A common feature of animal circadian clocks is the progressive phosphorylation of PERIOD (PER) proteins, which is highly dependent on casein kinase I/ (CKI/; termed DOUBLETIME [DBT] in Drosophila) and ultimately leads to the rapid degradation of hyperphosphorylated isoforms via a mechanism involving the F-box protein, β-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.

[Keywords: Circadian rhythms; Drosophila; PER; β-TrCP/SLIMB; CK1/DBT; F-box protein; phosphorylation]

Received April 9, 2008; revised version accepted May 9, 2008.

E-MAIL edery{at}cabm.rutgers.edu; FAX (732) 235-5318.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1682708.

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