CRY Drives Cyclic CK2-Mediated BMAL1 Phosphorylation to Control the Mammalian Circadian Clock

Intracellular circadian clocks,composed of clock genes that act in transcription-translation feedback loops,drive global rhythmic expression of the mammalian transcriptome and allow an organism to anticipate to the momentum of the day. using a novel clock-perturbing peptide,we established a pivotal role for casein kinase (ck)-2-mediated circadian bmal1-ser90 phosphorylation (bmal1-p) in regulating central and peripheral core clocks. subsequent analysis of the underlying mechanism showed a novel role of cry as a repressor for protein kinase. co-immunoprecipitation experiments and real-time monitoring of protein–protein interactions revealed that cry-mediated periodic binding of ck2β to bmal1 inhibits bmal1-ser90 phosphorylation by ck2α. the fad binding domain of cry1,two c-terminal bmal1 domains,and particularly bmal1-lys537 acetylation/deacetylation by clock/sirt1,were shown to be critical for cry-mediated bmal1–ck2β binding. reciprocally,bmal1-ser90 phosphorylation is prerequisite for bmal1-lys537 acetylation. we propose a dual negative-feedback model in which a cry-dependent ck2-driven posttranslational bmal1–p-bmal1 loop is an integral part of the core clock oscillator. © 2015 tamaru et al.