Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch
Copyright policy )Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch
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.
- University of California, San Diego United States
- National University of Singapore Singapore
- Duke Medical Center United States
- University of California, Santa Cruz United States
- Duke University Hospital United States
Biomedical and clinical sciences, Structural Biology and Molecular Biophysics, Molecular Dynamics Simulation (mesh), Casein Kinase I (mesh), Allosteric Regulation (mesh), 31 Biological sciences (for-2020), Animals (mesh), structural biology, Biology (General), Phosphorylation, Humans (mesh), Drosophila (mesh), Casein Kinase I, Period Circadian Proteins (mesh), Generic health relevance (hrcs-hc), Q, R, Period Circadian Proteins, Biological Sciences, Circadian Rhythm, Biological sciences, mouse cell culture, in vitro biochemistry, Medicine, Drosophila, Sleep Research, 570, Circadian Rhythm (mesh), QH301-705.5, 1.1 Normal biological development and functioning, Science, 0601 Biochemistry and Cell Biology (for), 610, Molecular Dynamics Simulation, Allosteric Regulation, Underpinning research, 42 Health sciences (for-2020), molecular biophysics, Animals, Humans, Sleep Research (rcdc), human, mouse, human cell culture, 1.1 Normal biological development and functioning (hrcs-rac), HEK293 Cells (mesh), 31 Biological Sciences (for-2020), Phosphorylation (mesh), Health sciences, protiens, 3101 Biochemistry and Cell Biology (for-2020), HEK293 Cells, 32 Biomedical and clinical sciences (for-2020), Biochemistry and Cell Biology, Generic health relevance
Biomedical and clinical sciences, Structural Biology and Molecular Biophysics, Molecular Dynamics Simulation (mesh), Casein Kinase I (mesh), Allosteric Regulation (mesh), 31 Biological sciences (for-2020), Animals (mesh), structural biology, Biology (General), Phosphorylation, Humans (mesh), Drosophila (mesh), Casein Kinase I, Period Circadian Proteins (mesh), Generic health relevance (hrcs-hc), Q, R, Period Circadian Proteins, Biological Sciences, Circadian Rhythm, Biological sciences, mouse cell culture, in vitro biochemistry, Medicine, Drosophila, Sleep Research, 570, Circadian Rhythm (mesh), QH301-705.5, 1.1 Normal biological development and functioning, Science, 0601 Biochemistry and Cell Biology (for), 610, Molecular Dynamics Simulation, Allosteric Regulation, Underpinning research, 42 Health sciences (for-2020), molecular biophysics, Animals, Humans, Sleep Research (rcdc), human, mouse, human cell culture, 1.1 Normal biological development and functioning (hrcs-rac), HEK293 Cells (mesh), 31 Biological Sciences (for-2020), Phosphorylation (mesh), Health sciences, protiens, 3101 Biochemistry and Cell Biology (for-2020), HEK293 Cells, 32 Biomedical and clinical sciences (for-2020), Biochemistry and Cell Biology, Generic health relevance
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