Article ; Online: CRY Drives Cyclic CK2-Mediated BMAL1 Phosphorylation to Control the Mammalian Circadian Clock.
2015 Volume 13, Issue 11, Page(s) e1002293
Abstract: ... for casein kinase (CK)-2-mediated circadian BMAL1-Ser90 phosphorylation (BMAL1-P) in regulating central and ... acetylation/deacetylation by CLOCK/SIRT1, were shown to be critical for CRY-mediated BMAL1-CK2β binding ... interactions revealed that CRY-mediated periodic binding of CK2β to BMAL1 inhibits BMAL1-Ser90 phosphorylation ...
| 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. |
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| MeSH term(s) | ARNTL Transcription Factors/chemistry ; ARNTL Transcription Factors/genetics ; ARNTL Transcription Factors/metabolism ; Animals ; Casein Kinase II/chemistry ; Casein Kinase II/genetics ; Casein Kinase II/metabolism ; Cell Line ; Cells, Cultured ; Circadian Clocks ; Cryptochromes/chemistry ; Cryptochromes/genetics ; Cryptochromes/metabolism ; Embryo, Mammalian/cytology ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mutation ; Phosphorylation ; Protein Interaction Domains and Motifs ; Protein Processing, Post-Translational ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism |
| Chemical Substances | ARNTL Transcription Factors ; Bmal1 protein, mouse ; Cry1 protein, mouse ; Cry2 protein, mouse ; Cryptochromes ; Recombinant Fusion Proteins ; Recombinant Proteins ; CSNK2A1 protein, human (EC 2.7.11.1) ; Casein Kinase II (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2015-11-12 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2126776-5 |
| ISSN | 1545-7885 ; 1544-9173 |
| ISSN (online) | 1545-7885 |
| ISSN | 1544-9173 |
| DOI | 10.1371/journal.pbio.1002293 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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