title: CRY Drives Cyclic CK2-Mediated BMAL1 Phosphorylation to Control the Mammalian Circadian Clock.
abstract: 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.
authors.affiliation: Department of Physiology and Advanced Research Center for Medical Science, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Teruya
authors.initials: T
authors.lastname: Tamaru
authors.affiliation: Department of Chemistry, The University of Tokyo, Tokyo, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Department of Chemistry, The University of Tokyo, Tokyo, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Honda
authors.affiliation: Laboratory of Gene Regulation Research, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan.
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Nakahata
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sassone-Corsi
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.affiliation: Department of Chemistry, The University of Tokyo, Tokyo, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Physiology and Advanced Research Center for Medical Science, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Takamatsu
mesh_terms: D056930:ARNTL Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D047390:Casein Kinase II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D057906:Circadian Clocks; D056931:Cryptochromes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II