LAUSR

“Everything has an appointed season, and a time for every activity under heaven” (Ecclesiastes 3:1). To better satisfy the demands of living in a cyclical world, organisms from bacteria to humans contain genetically encoded instructions for producing biological time-keeping devices, known as circadian (approximately 24 h) clocks. The first circadian clock gene identified was period (per) in Drosophila (fruit flies) (1), shortly thereafter followed by frequency (frq) in fungi (Neurospora) (2). Later work showed that mammalian clocks are also PER based, having three types (Per1, 2, and 3). PER and FRQ proteins share little amino acid sequence similarity but follow a remarkably similar 24-h life cycle (reviewed in refs. 3–5). Each day is marked by a predictable upswing in the production of newly synthesized PER and FRQ proteins that slowly undergo progressive increases in the addition of negatively charged phosphate groups (a process called phosphorylation) until some 18 to 20 h later when they reach maximally hyperphosphorylated states, a signal that triggers their rapid degradation. This 24-h choreography of phosphorylation/degradation gates when and for how long PER and FRQ function as negative Fig. 1. Casein kinase 1 works with functionally similar modules on PER and FRQ to drive their slow conversion from compact nonphosphorylated forms to extended hyperphosphorylated forms over a daily time scale, despite randomness in pathways to hyperphosphorylation (the beginnings of two random paths are indicated by the dice). Conserved modules include long stretches of highly disordered regions attached to a centrally located CK1 binding site. Increased phosphorylation by CK1 leads to electrostatic repulsion that force more open conformations, eventually facilitating the rapid degradation of PER and FRQ, which helps set the daily timing for the next round of PER and FRQ synthesis (not shown). Adapted from ref. 7.