Details

Autor(en) / Beteiligte

• Tamaru, Teruya
• Hattori, Mitsuru
• Honda, Kousuke
• Nakahata, Yasukazu
• Sassone-Corsi, Paolo
• van der Horst, Gijsbertus T J
• Ozawa, Takeaki
• Takamatsu, Ken
• Taghert, Paul H.

Titel

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

Ist Teil von

• PLoS biology, 2015-11, Vol.13 (11), p.e1002293-e1002293

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.