Characterizing Time-of-Day Conformational Changes in the Intrinsically Disordered Proteins of the Circadian Clock

Pelham, Jacqueline F.; Mosier, Alexander E.; Hurley, Jennifer M.

doi:10.1016/bs.mie.2018.08.024

Cited by 10 publications

(32 citation statements)

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“…The codons composing the frq transcript are non-optimal, which improves FRQ's co-translational folding (Zhou et al, 2013), and FRQ's disordered protein structure is also stabilized by its binding partner FRH (Hurley et al, 2013). Mammalian PER2 is also largely intrinsically disordered, and indeed circadian clock proteins across species have large stretches of intrinsic disorder which are in the early stages of functional characterization (Pelham et al, 2020;Pelham et al, 2018) (reviewed in: (Partch, 2020)). These data document the complexity of post-transcriptional regulation of clock components, and this study demonstrates that even non-rhythmic clock transcripts such as CKI are under tight regulation that is essential for normal clock function.…”

Section: Discussionmentioning

confidence: 99%

PRD-2 directly regulates casein kinase I and counteracts nonsense-mediated decay in the Neurospora circadian clock

Kelliher

Lambreghts

Xiang

et al. 2020

eLife

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Circadian clocks in fungi and animals are driven by a functionally conserved transcription–translation feedback loop. In Neurospora crassa, negative feedback is executed by a complex of Frequency (FRQ), FRQ-interacting RNA helicase (FRH), and casein kinase I (CKI), which inhibits the activity of the clock’s positive arm, the White Collar Complex (WCC). Here, we show that the prd-2 (period-2) gene, whose mutation is characterized by recessive inheritance of a long 26 hr period phenotype, encodes an RNA-binding protein that stabilizes the ck-1a transcript, resulting in CKI protein levels sufficient for normal rhythmicity. Moreover, by examining the molecular basis for the short circadian period of upf-1prd-6 mutants, we uncovered a strong influence of the Nonsense-Mediated Decay pathway on CKI levels. The finding that circadian period defects in two classically derived Neurospora clock mutants each arise from disruption of ck-1a regulation is consistent with circadian period being exquisitely sensitive to levels of casein kinase I.

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Section: Discussionmentioning

confidence: 99%

PRD-2 directly regulates casein kinase I and counteracts nonsense-mediated decay in the Neurospora circadian clock

Kelliher

Lambreghts

Xiang

et al. 2020

eLife

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“…A good example of this lies in the lack of sequence conservation of the negative arm of the circadian clock, which is one of the reasons it has been difficult to discern the mechanism of action of the negative arm proteins [46,47]. However, while there is little sequence conservation, one commonality in the negative arm proteins of eukaryotic TTFLs is in the conservation of intrinsic disorder in negative arm proteins [48][49][50] (Fig. 2).…”

Section: Circadian Output and Conserved Molecular Oscillatorsmentioning

confidence: 99%

“…This includes many of the biochemical activities assigned to clock proteins and the first experimental evidence of negative feedback oscillations, which was demonstrated with the frequency gene (reviewed in [49]). Neurospora continues to serve as an efficient model organism for circadian characterization from the molecular to "omics" scale [22,48,[66][67][68]. Notably, Neurospora was the first organism in which IDPs were demonstrated to play a role in the clock.…”

Section: Neurospora Crassa As a Circadian Model Organismmentioning

confidence: 99%

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Intrinsic disorder is an essential characteristic of components in the conserved circadian circuit

2020

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Introduction 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. Main body In this work, we focus on the extent of intrinsic disorder in the circadian clock and its potential mechanistic role in circadian timing. We highlight the conservation of disorder by quantifying the extent of computationally-predicted protein disorder in the core clock of the key eukaryotic circadian model organisms Drosophila melanogaster, Neurospora crassa, and Mus musculus. We further examine previously published work, as well as feature novel experimental evidence, demonstrating that the core negative arm circadian period drivers FREQUENCY (Neurospora crassa) and PERIOD-2 (PER2) (Mus musculus), possess biochemical characteristics of intrinsically disordered proteins. Finally, we discuss the potential contributions of the inherent biophysical principals of intrinsically disordered proteins that may explain the vital mechanistic roles they play in the clock to drive their broad evolutionary conservation in circadian timekeeping. Conclusion The pervasive conservation of disorder amongst the clock in the crown eukaryotes suggests that disorder is essential for optimal circadian timing from fungi to animals, providing vital homeostatic cellular maintenance and coordinating organismal physiology across phylogenetic kingdoms. Graphical abstract

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“…FRQ is an intrinsically disordered protein encoded by non-optimal codons to improve its co-translational folding (Zhou et al, 2013), and FRQ structure is also stabilized by its binding partner FRH (Hurley et al, 2013). PER2 is also largely intrinsically disordered, and indeed circadian clock proteins across species have large stretches of intrinsic disorder which are in the early stages of functional characterization (Pelham et al, 2020; Pelham et al, 2018) (reviewed in: (Partch, 2020)). Finally, an extremely conserved feature of the clock’s negative arm is progressive phosphorylation and alteration of function over time (reviewed in: (Dunlap and Loros, 2018)).…”

Section: Introductionmentioning

confidence: 99%

Nonsense mediated decay and a novel protein Period-2 regulatecasein kinase Iin an opposing manner to control circadian period inNeurospora crassa

Kelliher

Lambreghts

Xiang

et al. 2020

Preprint

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Circadian clocks in fungi and animals are driven by a functionally conserved transcription-translation feedback loop. In Neurospora crassa, negative feedback is executed by a complex of Frequency (FRQ), FRQ-interacting RNA helicase (FRH), and Casein Kinase I (CKI), which inhibits the activity of the clock's positive arm, the White Collar Complex (WCC). Here, we show that the period-2 gene, whose mutation is characterized by recessive inheritance of a long 26-hour period phenotype, encodes an RNA-binding protein that stabilizes the ck-1a transcript, resulting in CKI protein levels sufficient for normal rhythmicity. Moreover, by examining the molecular basis for the short circadian period of period-6 mutants, we uncovered a strong influence of the Nonsense Mediated Decay pathway on CKI levels. The finding that circadian period defects in two classically-derived Neurospora clock mutants each arise from disruption of ck-1a regulation is consistent with circadian period being exquisitely sensitive to levels of casein kinase I.

show abstract

Characterizing Time-of-Day Conformational Changes in the Intrinsically Disordered Proteins of the Circadian Clock

Cited by 10 publications

References 83 publications

PRD-2 directly regulates casein kinase I and counteracts nonsense-mediated decay in the Neurospora circadian clock

PRD-2 directly regulates casein kinase I and counteracts nonsense-mediated decay in the Neurospora circadian clock

Intrinsic disorder is an essential characteristic of components in the conserved circadian circuit

Nonsense mediated decay and a novel protein Period-2 regulatecasein kinase Iin an opposing manner to control circadian period inNeurospora crassa

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