Journal Article

Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch

Yee, Lauren E, Freeberg, Alfred M, Tripathi, Sarvind, Virshup, David M, Hunt, Sabrina R, Ricci, Clarisse G, Pelofsky, Rebecca S, Philpott, Jonathan M, Partch, Carrie L, Narasimamurthy, Rajesh

2020

Overview

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 Drosophila 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.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Allosteric properties / Allosteric Regulation / Animals / BASIC BIOLOGICAL SCIENCES / Binding sites / Casein / Casein kinase I / Casein Kinase I - genetics / Casein Kinase I - metabolism / Circadian Rhythm / Circadian rhythms / Computer applications / Conformation / Drosophila / Evolutionary conservation / Gene expression / HEK293 Cells / human cell culture / Humans / in vitro biochemistry / Insects / Kinases / Molecular Dynamics Simulation / mouse cell culture / Mutation / Peptides / Period 2 protein / Period Circadian Proteins - metabolism / Phosphorylation / Physiology / Post-translation / Proteins / protiens / Sleep / Structural Biology and Molecular Biophysics