The phosphorylation switch that regulates ticking of the circadian clock

• Published in: Molecular cell 2021-03, Vol.81 (6), p.1133-1146
• Main Authors: Narasimamurthy, Rajesh, Virshup, David M.
• Format: Article
• Language: English
• Subjects: Animals; Casein Kinase I - genetics; Casein Kinase I - metabolism; Circadian Clocks - physiology; Circadian Rhythm - physiology; Humans; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Phosphorylation - physiology
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.01.006

In our 24/7 well-lit world, it’s easy to skip or delay sleep to work, study, and play. However, our circadian rhythms are not easily fooled; the consequences of jet lag and shift work are many and severe, including metabolic, mood, and malignant disorders. The internal clock that keeps track of time has at its heart the reversible phosphorylation of the PERIOD proteins, regulated by isoforms of casein kinase 1 (CK1). In-depth biochemical, genetic, and structural studies of these kinases, their mutants, and their splice variants have combined over the past several years to provide a robust understanding of how the core clock is regulated by a phosphoswitch whereby phosphorylation of a stabilizing site on PER blocks phosphorylation of a distant phosphodegron. The recent structure of a circadian mutant form of CK1 implicates an internal activation loop switch that regulates this phosphoswitch and points to new approaches to regulation of the clock. Narasimamurthy and Virshup review how casein kinase 1 regulates the PERIOD proteins that lie at the heart of our molecular circadian clock. The phosphoswitch mechanism that controls PER2 protein stability is influenced by the kinase activation loop, whose positioning may be regulated by both internal and external stimuli.