Just-So Stories and Origin Myths: Phosphorylation and Structural Disorder in Circadian Clock Proteins

Abstract

Some longstanding dogmas in the circadian field warrant reexamination in light of recent studies focused on the role of post-translational modifications and intrinsic disorder in core circadian clock proteins of mice and fungi. Such dogmas include the role of turnover in circadian feedback loops and the origin myths describing evolutionary relatedness among circadian clocks. In this Essay, the authors recapitulate recent findings on circadian clock protein regulation by taking an unconventional approach in the form of a dialog between Wizard and Apprentice.

Phosphorylation Hypothesis of Sleep

“…In addition, PER/FRQ and their responsible kinase CKI, as well as other binding partners, form a macromolecular complex ( Aryal et al, 2017 ; Liu et al, 2019 ), the status of which (e.g., binding affinity of each component) may be changed slowly by multisite phosphorylation within the complex. In a sense, the slow dynamics produced by the collective and cooperative interaction of protein complexes driven by multisite phosphorylation may act as a timer to count the length of a 24-h period in eukaryotes ( Larrondo et al, 2015 ; Dunlap and Loros, 2018 ; Ode and Ueda, 2018 ; Diernfellner and Brunner, 2020 ; Loros, 2020 ; Partch, 2020 ).…”

Non-transcriptional processes in circadian rhythm generation

“…In positing a post-translational model for circadian rhythm generation, it is informative to consider the implications for the evolutionary origin of 24-hour timekeeping. Each of the essential post-translational timekeeping mechanisms discussed above is strongly implicated in the regulation of circadian rhythms in the fungal and green lineages, functioning similarly to determine the activity of the clock proteins in other eukaryotic kingdoms despite their transcription factor substrates not being thought to share a common origin [ 30 , 192 • ]. Thus, a primarily post-translational cellular clock mechanism suggests a divergent evolutionary history because critical post-translational determinants of 24-hour periodicity are highly conserved (proteasomes, casein kinases, glycogen synthase kinases and protein phosphatases), whilst the identities of TTFL components are poorly conserved.…”

Circadian Proteomic Analysis Uncovers Mechanisms of Post-Transcriptional Regulation in Metabolic Pathways

“…The regulatory architecture of the clock is conserved between fungi and animals; at its core is a transcription-translation negative feedback loop (TTFL) involving a heterodimeric transcription-factor complex that functions as the positive arm and a distinct protein complex, the negative arm, whose function is to inhibit the transcriptional activity of the positive arm (Figure 1A; Dunlap and Loros, 2018; Hurley et al, 2016). …”