NEMO/NLK Phosphorylates PERIOD to Initiate a Time-Delay Phosphorylation Circuit that Sets Circadian Clock Speed

被引:139
作者
Chiu, Joanna C. [1 ,2 ]
Ko, Hyuk Wan [1 ]
Edery, Isaac [1 ]
机构
[1] Rutgers State Univ, Ctr Adv Biotechnol & Med, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA
[2] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA
关键词
SLEEP PHASE SYNDROME; DROSOPHILA CLOCK; PROTEIN; GENE; MELANOGASTER; MUTATION; KINASE; NEUROSPORA; DOUBLETIME; MUTANTS;
D O I
10.1016/j.cell.2011.04.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The speed of circadian clocks in animals is tightly linked to complex phosphorylation programs that drive daily cycles in the levels of PERIOD (PER) proteins. Using Drosophila, we identify a time-delay circuit based on hierarchical phosphorylation that controls the daily downswing in PER abundance. Phosphorylation by the NEMO/NLK kinase at the "per-short" domain on PER stimulates phosphorylation by DOUBLETIME (DBT/CK1 delta/epsilon) at several nearby sites. This multisite phosphorylation operates in a spatially oriented and graded manner to delay progressive phosphorylation by DBT at other more distal sites on PER, including those required for recognition by the F box protein SLIMB/beta-TrCP and proteasomal degradation. Highly phosphorylated PER has a more open structure, suggesting that progressive increases in global phosphorylation contribute to the timing mechanism by slowly increasing PER susceptibility to degradation. Our findings identify NEMO as a clock kinase and demonstrate that long-range interactions between functionally distinct phospho-clusters collaborate to set clock speed.
引用
收藏
页码:357 / 370
页数:14
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