activating per repressor through a dbt-directed phosphorylation switch激活抑制因子通过dbt-directed磷酸化开关.pdfVIP

PLoS BIOLOGY Activating PER Repressor through a DBT-Directed Phosphorylation Switch ¨ ¤ * Saul Kivimae , Lino Saez, Michael W. Young Laboratory of Genetics, The Rockefeller University, New York, New York, United States of America Protein phosphorylation plays an essential role in the generation of circadian rhythms, regulating the stability, activity, and subcellular localization of certain proteins that constitute the biological clock. This study examines the role of the protein kinase Doubletime (DBT), a Drosophila ortholog of human casein kinase I (CKI)e/d. An enzymatically active DBT protein is shown to directly phosphorylate the Drosophila clock protein Period (PER). DBT-dependent phosphorylation sites are identified within PER, and their functional significance is assessed in a cultured cell system and in vivo. The perS mutation, which is associated with short-period (19-h) circadian rhythms, alters a key phosphorylation target within PER. Inspection of this and neighboring sequence variants indicates that several DBT-directed phosphorylations regulate PER activity in an integrated fashion: Alternative phosphorylations of two adjoining sequence motifs appear to be associated with switch-like changes in PER stability and repressor function. ¨ Citation: Kivimae S, Saez L, Young MW (2008) Activating PER repressor through a DBT-directed phosphorylation switch. PLoS Biol 6(7): e183. doi:10.1371/journal.pbio. 0060183 Introduction disorder may reflect altered phosphorylation of PER2, as FASPS has also been associated with mutation of a putat