Casein Kinase 1 Dynamics Underlie Substrate Selectivity and the PER2 Circadian Phosphoswitch

Overview

Journal Elife

Specialty Biology

Date 2020 Feb 12

PMID 32043967

Citations 34

Authors

Jonathan M Philpott

Rajesh Narasimamurthy

Clarisse G Ricci

Alfred M Freeberg

Sabrina R Hunt

Lauren E Yee

Rebecca S Pelofsky

Sarvind Tripathi

David M Virshup

Carrie L Partch

Affiliations

Soon will be listed here.

Abstract

Post-translational control of PERIOD stability by Casein Kinase 1δ and ε (CK1) plays a key regulatory role in metazoan circadian rhythms. Despite the deep evolutionary conservation of CK1 in eukaryotes, little is known about its regulation and the factors that influence substrate selectivity on functionally antagonistic sites in PERIOD that directly control circadian period. Here we describe a molecular switch involving a highly conserved anion binding site in CK1. This switch controls conformation of the kinase activation loop and determines which sites on mammalian PER2 are preferentially phosphorylated, thereby directly regulating PER2 stability. Integrated experimental and computational studies shed light on the allosteric linkage between two anion binding sites that dynamically regulate kinase activity. We show that period-altering kinase mutations from humans to differentially modulate this activation loop switch to elicit predictable changes in PER2 stability, providing a foundation to understand and further manipulate CK1 regulation of circadian rhythms.

Citing Articles

Markovian State Models uncover Casein Kinase 1 dynamics that govern circadian period.

Ricci C, Philpott J, Torgrimson M, Freeberg A, Narasimamurthy R, de Barros E bioRxiv. 2025; .

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Development of compounds for targeted degradation of mammalian cryptochrome proteins.

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Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein kinase 1.

Harold R, Tulsian N, Narasimamurthy R, Yaitanes N, Ayala Hernandez M, Lee H Proc Natl Acad Sci U S A. 2024; 121(41):e2415567121.

PMID: 39356670 PMC: 11474029. DOI: 10.1073/pnas.2415567121.

Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein Kinase 1.

Harold R, Tulsian N, Narasimamurthy R, Yaitanes N, Ayala Hernandez M, Lee H bioRxiv. 2024; .

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Phosphorylation of DNA-binding domains of CLOCK-BMAL1 complex for PER-dependent inhibition in circadian clock of mammalian cells.

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PMID: 38805270 PMC: 11161756. DOI: 10.1073/pnas.2316858121.

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