CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch.
Published
Journal Article
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.
Full Text
Duke Authors
Cited Authors
- Narasimamurthy, R; Hunt, SR; Lu, Y; Fustin, J-M; Okamura, H; Partch, CL; Forger, DB; Kim, JK; Virshup, DM
Published Date
- June 5, 2018
Published In
Volume / Issue
- 115 / 23
Start / End Page
- 5986 - 5991
PubMed ID
- 29784789
Pubmed Central ID
- 29784789
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.1721076115
Language
- eng
Conference Location
- United States