CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch

Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by casein kinase 1 (CK1), an essential clock component...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 23; p. 5986
Main Authors: Narasimamurthy, Rajesh, Hunt, Sabrina R, Lu, Yining, Fustin, Jean-Michel, Okamura, Hitoshi, Partch, Carrie L, Forger, Daniel B, Kim, Jae Kyoung, Virshup, David M
Format: Journal Article
Language:English
Published: United States 05.06.2018
Subjects:
Animals
Casein Kinase Idelta - metabolism
Casein Kinase Iepsilon - metabolism
Circadian Rhythm - physiology
HEK293 Cells
Humans
Mice
Period Circadian Proteins - genetics
Period Circadian Proteins - metabolism
Phosphorylation
cell regulation
circadian rhythms
protein kinase
ISSN:1091-6490, 1091-6490
Online Access:Get more information
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Summary:Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by casein kinase 1 (CK1), an essential clock component that is conserved from algae to humans. These subsequent phosphorylations stabilize PER2, delay its degradation, and lengthen the period of the circadian clock. Here, we perform a comprehensive biochemical and biophysical analysis of mouse PER2 (mPER2) priming phosphorylation and demonstrate, surprisingly, that CK1δ/ε is indeed the priming kinase. We find that both CK1ε and a recently characterized CK1δ2 splice variant more efficiently prime mPER2 for downstream phosphorylation in cells than the well-studied splice variant CK1δ1. While CK1 phosphorylation of PER2 was previously shown to be robust to changes in the cellular environment, our phosphoswitch mathematical model of circadian rhythms shows that the CK1 carboxyl-terminal tail can allow the period of the clock to be sensitive to cellular signaling. These studies implicate the extreme carboxyl terminus of CK1 as a key regulator of circadian timing.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1721076115