Decoupling PER phosphorylation, stability and rhythmic expression from circadian clock function by abolishing PER-CK1 interaction

Robust rhythms of abundances and phosphorylation profiles of PERIOD proteins were thought be the master rhythms that drive mammalian circadian clock functions. PER stability was proposed to be a major determinant of period length. In mammals, CK1 forms stable complexes with PER. Here we identify the...

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Published in:Nature communications 2022-07, Vol.13 (1), p.3991-3991, Article 3991
Main Authors: An, Yang, Yuan, Baoshi, Xie, Pancheng, Gu, Yue, Liu, Zhiwei, Wang, Tao, Li, Zhihao, Xu, Ying, Liu, Yi
Format: Article
Language:English
Subjects:
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Biological clocks
BMAL1 protein
Circadian rhythm
Circadian rhythms
Decoupling
Feedback
Humanities and Social Sciences
Locomotor activity
Mammals
multidisciplinary
Mutation
Negative feedback
Phosphorylation
Proteins
Robustness
Scaffolds
Science
Science (multidisciplinary)
Stability
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Summary:Robust rhythms of abundances and phosphorylation profiles of PERIOD proteins were thought be the master rhythms that drive mammalian circadian clock functions. PER stability was proposed to be a major determinant of period length. In mammals, CK1 forms stable complexes with PER. Here we identify the PER residues essential for PER-CK1 interaction. In cells and in mice, their mutation abolishes PER phosphorylation and CLOCK hyperphosphorylation, resulting in PER stabilization, arrhythmic PER abundance and impaired negative feedback process, indicating that PER acts as the CK1 scaffold in circadian feedback mechanism. Surprisingly, the mutant mice exhibit robust short period locomotor activity and other physiological rhythms but low amplitude molecular rhythms. PER-CK1 interaction has two opposing roles in regulating CLOCK-BMAL1 activity. These results indicate that the circadian clock can function independently of PER phosphorylation and abundance rhythms due to another PER-CRY-dependent feedback mechanism and that period length can be uncoupled from PER stability. PERIOD proteins, the core components of the mammalian circadian clock, act as the CK1 scaffold in the negative feedback process. Surprisingly, the mouse circadian clock can function independent of PER phosphorylation and PER abundance rhythms.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-31715-4