Pelham, J.F., Dunlap, J.C. & Hurley, J.M. Intrinsic disorder is an essential characteristic of components in the conserved circadian circuit. Cell Commun Signal 18, 181 (2020). https://doi.org/10.1186/s12964-020-00658-y
The circadian circuit, a roughly 24 h molecular feedback loop, or clock, is conserved from bacteria to animals and allows for enhanced organismal survival by facilitating the anticipation of the day/night cycle. With circadian regulation reportedly impacting as high as 80% of protein coding genes in higher eukaryotes, the protein-based circadian clock broadly regulates physiology and behavior. Due to the extensive interconnection between the clock and other cellular systems, chronic disruption of these molecular rhythms leads to a decrease in organismal fitness as well as an increase of disease rates in humans. Importantly, recent research has demonstrated that proteins comprising the circadian clock network display a significant amount of intrinsic disorder.
With this sizeable amount of gene regulation, and by extension physiology, it is no surprise that the disruption of circadian rhythms has been noted to lead to decreased physiological fitness [3, 26]. Chronic circadian disruption has been linked with many disease states, including a higher risk of obesity, heart disease, diabetes, depression, and cancer [27,28,29,30,31]. Furthermore, genes under the control of the circadian clock show a strong correlation with disease-associated genes and out of the top 100 selling drugs in the US, 56 target a gene under circadian regulation (including the top 7) . With 20% of the working population subject to “shift work” and the widespread use of digital screens and blue-light-emitting devices, circadian disruption is a growing cause of preventable disease [33, 34].
Conversely, methods of circadian intervention and treatment have been developed, including the application of light-based therapy for dementia-related pathologies. For example, Alzheimer’s disease commonly results in disturbances to circadian rhythms, leading to increased deposition of the plaques that exacerbate Alzheimer’s disease pathology. This in turn leads to further dysregulation of the circadian clock, thus creating a positive feedback loop with negative effects on the pathology and progression of Alzheimer’s disease. As a treatment modality, optimized circadian entrainment lighting for patients with Alzheimer’s disease has been implemented in assisted living facilities and has been shown to improve behavior, sleep, and mood . In summary, the circadian system has been shown to play an essential role in organismal health and physiology, though many questions still remain detailing its extensive reaches into the cell.
IDPs have been suggested to serve important roles in finely tuning the circadian regulatory circuit through post-transcriptional regulation, multiple interacting partners, and many other mechanisms. We have discussed examples of disorder in the clock and how they underlie the mechanisms for several of the phenomena in the circadian system from timing, to the regulation of output, to providing the capacity for the clock to respond to cellular conditions. Considering the complexity and deep reaches of the molecular circadian circuit, disorder presents an essential and inherent mechanism of biological control, supported by the conservation of protein disorder in clocks from lower to higher eukaryotes.