CRY Drives Cyclic CK2-Mediated BMAL1 Phosphorylation to Control the Mammalian Circadian Clock e1002293

• Published in: PLoS biology Vol. 13; no. 11
• Main Authors: Tamaru, Teruya, Hattori, Mitsuru, Honda, Kousuke, Nakahata, Yasukazu, Sassone-Corsi, Paolo, Horst, J vander, Ozawa, Takeaki, Takamatsu, Ken
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 01-11-2015
• Subjects: Behavior; Circadian rhythm; Experiments; Kinases; Localization; Molecular weight; Phosphorylation; Proteins; RNA polymerase; Rodents; Transcription factors
• ISSN: 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1002293

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 CK2[Beta] to BMAL1 inhibits BMAL1-Ser90 phosphorylation by CK2[alpha] . 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-CK2[Beta] 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.