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

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 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.

p63 uses a switch-like mechanism to set the threshold for induction of apoptosis

“…To investigate the mode of action, we analyzed the phosphorylation kinetics of individual sites within a peptide that included all phosphorylation sites for CHK2 and CK1 (phosphorylation activation domain, PAD) located N-terminal to the transactivation inhibitory domain (TID) 28,29 . For these investigations, we used NMR spectroscopy [30][31][32][33][34][35][36] based on a gradient-selected Band-selective excitation short-transient transverse relaxation-optimized spectroscopy (BEST-TROSY) pulse sequence 37 , allowing us to restrict the measurement time of each 2D spectrum to 120 s. Phosphorylation of S582 by MapKap kinase 2 (MK2), which recognizes the same phosphorylation sequence as CHK2, resulted in new resonance in the TROSY spectrum and loss of the original S582 signal (Extended Data Fig. 1a).…”

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

“…Whilst the majority of identified IMiD neo-substrates appear to be zinc-finger transcription factors (2,5,6), lenalidomide has also been shown to induce the degradation of the serine/threonine kinase CK1 (7). Casein kinase 1 isoforms (, -like, , , 1, 2 and 3) are a family of serine/threonine protein kinases which control many cellular processes, including Wnt signalling, circadian rhythms, calcium signalling, cell division and responses to DNA damage (8)(9)(10)(11). Lenalidomide binds to a -hairpin loop in the kinase N-lobe of CK1, bringing it into proximity of the Cul4A CRBN complex to facilitate its ubiquitylation and subsequent proteasomal degradation (12).…”

Multiple random phosphorylations in clock proteins provide long delays and switches

“…Self-sustained circadian oscillations require long delays and nonlinearities ("switches") [29,30]. Recent experiments suggest that slow and seemingly random phosphorylations of intrinsically disordered clock proteins control stability and function of clock protein complexes such as FFC in Neurospora and PER:CRY in mammals [18,25,70]). Since only few detailed quantitative data are available we compared several generic models describing linear processive phosphorylation, nonlinear distributive phosphorylation, and random phosphorylation.…”