scholarly journals Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jennifer L Fribourgh ◽  
Ashutosh Srivastava ◽  
Colby R Sandate ◽  
Alicia K Michael ◽  
Peter L Hsu ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Feedback Loop ◽  
Pas Domain ◽  
Transactivation Domain ◽  
Transcriptional Repressors ◽  
Circadian Period ◽  
Circadian Timing ◽  
Homology Region ◽  
Differential Binding ◽  
Differential Affinity

Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1.

scholarly journals Protein dynamics regulate distinct biochemical properties of cryptochromes in mammalian circadian rhythms

2019 ◽  
Author(s):  
Jennifer L. Fribourgh ◽  
Ashutosh Srivastava ◽  
Colby R. Sandate ◽  
Alicia K. Michael ◽  
Peter L. Hsu ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Feedback Loop ◽  
Structural Difference ◽  
Biochemical Properties ◽  
Pas Domain ◽  
Transactivation Domain ◽  
Transcriptional Repressors ◽  
Circadian Period ◽  
Differential Binding ◽  
Similar Affinity

SummaryCircadian rhythms are generated by a transcription-based feedback loop where CLOCK:BMAL1 drive transcription of their repressors (PER1/2, CRY1/2), which bind to CLOCK:BMAL1 to close the feedback loop with ~24-hour periodicity. Here we identify a key biochemical and structural difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. While both cryptochromes bind the BMAL1 transactivation domain with similar affinity to sequester it from coactivators, CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We identify a dynamic loop in the secondary pocket that regulates differential binding of cryptochromes to the PAS domain core. Notably, PER2 binding remodels this loop in CRY2 to enhance its affinity for CLOCK:BMAL1, explaining why CRY2 forms an obligate heterodimer with PER2, while CRY1 is capable of repressing CLOCK:BMAL1 both with and without PER2.

scholarly journals Survival is reduced when endogenous period deviates from 24 h in a non-human primate, supporting the circadian resonance theory

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Clara Hozer ◽  
Martine Perret ◽  
Samuel Pavard ◽  
Fabien Pifferi
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Microcebus Murinus ◽  
Circadian Period ◽  
Biological Functions ◽  
Resonance Theory ◽  
Aging Research ◽  
Mouse Lemurs ◽  
Living Organisms ◽  
Human Primate

Abstract Circadian rhythms are ubiquitous attributes across living organisms and allow the coordination of internal biological functions with optimal phases of the environment, suggesting a significant adaptive advantage. The endogenous period called tau lies close to 24 h and is thought to be implicated in individuals’ fitness: according to the circadian resonance theory, fitness is reduced when tau gets far from 24 h. In this study, we measured the endogenous period of 142 mouse lemurs (Microcebus murinus), and analyzed how it is related to their survival. We found different effects according to sex and season. No impact of tau on mortality was found in females. However, in males, the deviation of tau from 24 h substantially correlates with an increase in mortality, particularly during the inactive season (winter). These results, comparable to other observations in mice or drosophila, show that captive gray mouse lemurs enjoy better fitness when their circadian period closely matches the environmental periodicity. In addition to their deep implications in health and aging research, these results raise further ecological and evolutionary issues regarding the relationships between fitness and circadian clock.

Evolution Analysis of the Circadian Clock Protein KaiB

2013 ◽  
Vol 647 ◽  
pp. 391-395
Author(s):  
Liu Sen ◽  
Song Liu
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Feedback Loop ◽  
Circadian System ◽  
Circadian Rhythmicity ◽  
Physiological Functions ◽  
Clock System ◽  
Evolution Analysis ◽  
Clock Protein

Regulation of daily physiological functions with approximate a 24-hour periodicity, or circadian rhythms, is a characteristic of eukaryotes. So far, cyanobacteria are only known prokaryotes reported to possess circadian rhythmicity. The circadian system in cyanobacteria comprises both a post-translational oscillator (PTO) and a transcriptional/translational feedback loop (TTFL). The PTO can be reconstituted in vitro with three purified proteins (KaiA, KaiB, and KaiC) with the existence of ATP. Phase of the nanoclockwork has been associated with the phosphorylation states of KaiC, with KaiA promoting the phosphorylation of KaiC, and KaiB de-phosphorylating KaiC. Here we studied the evolution of the KaiB protein. The result will be helpful in understanding the evolution of the circadian clock system.

The Role of Light Sensitivity and Intrinsic Circadian Period in Predicting Individual Circadian Timing

2020 ◽  
Vol 35 (6) ◽  
pp. 628-640 ◽  
Author(s):  
Julia E. Stone ◽  
Elise M. McGlashan ◽  
Nina Quin ◽  
Kayan Skinner ◽  
Jessica J. Stephenson ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Circadian Clock ◽  
Response Curve ◽  
Mean Absolute Error ◽  
Absolute Error ◽  
Light Sensitivity ◽  
Circadian Period ◽  
Interindividual Differences ◽  
Circadian Timing ◽  
The Mean

There is large interindividual variability in circadian timing, which is underestimated by mathematical models of the circadian clock. Interindividual differences in timing have traditionally been modeled by changing the intrinsic circadian period, but recent findings reveal an additional potential source of variability: large interindividual differences in light sensitivity. Using an established model of the human circadian clock with real-world light recordings, we investigated whether changes in light sensitivity parameters or intrinsic circadian period could capture variability in circadian timing between and within individuals. Healthy participants ( n = 12, aged 18-26 years) underwent continuous light monitoring for 3 weeks (Actiwatch Spectrum). Salivary dim-light melatonin onset (DLMO) was measured each week. Using the recorded light patterns, a sensitivity analysis for predicted DLMO times was performed, varying 3 model parameters within physiological ranges: (1) a parameter determining the steepness of the dose-response curve to light ( p), (2) a parameter determining the shape of the phase-response curve to light ( K), and (3) the intrinsic circadian period ( tau). These parameters were then fitted to obtain optimal predictions of the three DLMO times for each individual. The sensitivity analysis showed that the range of variation in the average predicted DLMO times across participants was 0.65 h for p, 4.28 h for K, and 3.26 h for tau. The default model predicted the DLMO times with a mean absolute error of 1.02 h, whereas fitting all 3 parameters reduced the mean absolute error to 0.28 h. Fitting the parameters independently, we found mean absolute errors of 0.83 h for p, 0.53 h for K, and 0.42 h for tau. Fitting p and K together reduced the mean absolute error to 0.44 h. Light sensitivity parameters captured similar variability in phase compared with intrinsic circadian period, indicating they are viable targets for individualizing circadian phase predictions. Future prospective work is needed that uses measures of light sensitivity to validate this approach.

scholarly journals Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients

2010 ◽  
Vol 1 (1) ◽  
pp. 48-60 ◽  
Author(s):  
Christopher G. Scully ◽  
Abdoulaye Karaboué ◽  
Wei-Min Liu ◽  
Joseph Meyer ◽  
Pasquale F. Innominato ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Skin Temperature ◽  
Cancer Patients ◽  
Infrared Imaging ◽  
Core Body Temperature ◽  
Dynamic Assessment ◽  
Invasive Approach ◽  
Circadian Timing ◽  
Circadian Phase ◽  
Temperature Rhythms

Chronotherapeutics involve the administration of treatments according to circadian rhythms. Circadian timing of anti-cancer medications has been shown to improve treatment tolerability up to fivefold and double efficacy in experimental and clinical studies. However, the physiological and the molecular components of the circadian timing system (CTS), as well as gender, critically affect the success of a standardized chronotherapeutic schedule. In addition, a wrongly timed therapy or an excessive drug dose disrupts the CTS. Therefore, a non-invasive approach to accurately detect and monitor circadian rhythms is needed for a dynamic assessment of the CTS in order to personalize chronomodulated drug delivery schedule in cancer patients. Since core body temperature is a robust circadian biomarker, we recorded temperature at multiple locations on the skin of the upper chest and back of controls and cancer patients continuously. Variability in the circadian phase existed among patch locations in individual subjects over the course of 2–6 days, demonstrating the need to monitor multiple skin temperature locations to determine the precise circadian phase. Additionally, we observed that locations identified by infrared imaging as relatively cool had the largest 24 h temperature variations. Disruptions in skin temperature rhythms during treatment were found, pointing to the need to continually assess circadian timing and personalize chronotherapeutic schedules.

scholarly journals Early doors (Edo) mutant mouse reveals the importance of period 2 (PER2) PAS domain structure for circadian pacemaking

2016 ◽  
Vol 113 (10) ◽  
pp. 2756-2761 ◽  
Author(s):  
Stefania Militi ◽  
Elizabeth S. Maywood ◽  
Colby R. Sandate ◽  
Johanna E. Chesham ◽  
Alun R. Barnard ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Feedback Loop ◽  
Mutant Mouse ◽  
Protein Complexes ◽  
Causal Link ◽  
Structural Basis ◽  
Pas Domain ◽  
Period 2 ◽  
Clock Proteins ◽  
Functional Relevance

The suprachiasmatic nucleus (SCN) defines 24 h of time via a transcriptional/posttranslational feedback loop in which transactivation of Per (period) and Cry (cryptochrome) genes by BMAL1–CLOCK complexes is suppressed by PER–CRY complexes. The molecular/structural basis of how circadian protein complexes function is poorly understood. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced mutation, early doors (Edo), in the PER-ARNT-SIM (PAS) domain dimerization region of period 2 (PER2) (I324N) that accelerates the circadian clock of Per2Edo/Edo mice by 1.5 h. Structural and biophysical analyses revealed that Edo alters the packing of the highly conserved interdomain linker of the PER2 PAS core such that, although PER2Edo complexes with clock proteins, its vulnerability to degradation mediated by casein kinase 1ε (CSNK1E) is increased. The functional relevance of this mutation is revealed by the ultrashort (<19 h) but robust circadian rhythms in Per2Edo/Edo; Csnk1eTau/Tau mice and the SCN. These periods are unprecedented in mice. Thus, Per2Edo reveals a direct causal link between the molecular structure of the PER2 PAS core and the pace of SCN circadian timekeeping.

scholarly journals Generation of a Dominant-negative Mutant of Endothelial PAS Domain Protein 1 by Deletion of a Potent C-terminal Transactivation Domain

1999 ◽  
Vol 274 (44) ◽  
pp. 31565-31570 ◽  
Author(s):  
Koji Maemura ◽  
Chung-Ming Hsieh ◽  
Mukesh K. Jain ◽  
Shinya Fukumoto ◽  
Matthew D. Layne ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Pas Domain ◽  
Transactivation Domain ◽  
Domain Protein ◽  
Negative Mutant

scholarly journals Altered Affective Behaviors in Casein Kinase 1 Epsilon Mutant Mice

2020 ◽  
Author(s):  
Lili Zhou ◽  
Karrie Fitzpatrick ◽  
Christopher Olker ◽  
Martha H. Vitaterna ◽  
Fred W. Turek
Keyword(s):  
Circadian Rhythms ◽  
Casein Kinase ◽  
Circadian Period ◽  
Wild Type ◽  
Casein Kinase 1 ◽  
Phenotypic Differences ◽  
Affective Behaviors ◽  
Casein Kinase 1 Epsilon ◽  
Fear And Anxiety ◽  
Mutant Lines

AbstractAffective behaviors and mental health are profoundly affected by disturbances in circadian rhythms. Casein kinase 1 epsilon (CSNK1E) is an essential component of the core circadian clock. Mice with tau or null mutation of this gene have shortened and lengthened circadian period respectively. Here we examined anxiety-like, fear, and depressive-like behaviors in both male and female mice of these two different mutants. Compared with wild-type mice, we found reductions in fear and anxiety-like behaviors in both mutant lines and in both sexes, with the tau mutants exhibiting the greatest phenotypic changes. However, the depressive-like behaviors had distinct phenotypic patterns, with markedly less depressive-like behaviors in female null mutants, but not in tau mutants of either sex. To determine whether abnormal light entrainment of tau mutants to 24 hour light-dark cycles contributes to these phenotypic differences, we also examined these behaviors in tau mutants on a 20 hour light-dark cycle close to their endogenous circadian period. The normalized entrainment restored more wild-type-like behaviors for fear and anxiety, but it induced depressive-like behavior in tau mutant females. These data show that both mutations of Csnk1e broadly affect fear and anxiety-like behaviors, while the effects on depressive-like behavior vary with genetics, photoperiod, and sex, suggesting that the mechanisms by which Csnk1e affects fear and anxiety-like behaviors may be similar, but distinct from those affecting depressive-like behavior. Our study also provides experimental evidence in support of the hypothesis of beneficial outcomes from properly entrained circadian rhythms in terms of the anxiety-like and fear behaviors.

scholarly journals Roles of Neuropeptides, VIP and AVP, in the Mammalian Central Circadian Clock

2021 ◽  
Vol 15 ◽  
Author(s):  
Daisuke Ono ◽  
Ken-ichi Honma ◽  
Sato Honma
Keyword(s):  
Transcription Factors ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Cellular Networks ◽  
Clock Genes ◽  
Circadian System ◽  
Developmental Changes ◽  
Circadian Period ◽  
Functional Roles ◽  
Environmental Light

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Individual SCN cells exhibit intrinsic oscillations, and their circadian period and robustness are different cell by cell in the absence of cellular coupling, indicating that cellular coupling is important for coherent circadian rhythms in the SCN. Several neuropeptides such as arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) are expressed in the SCN, where these neuropeptides function as synchronizers and are important for entrainment to environmental light and for determining the circadian period. These neuropeptides are also related to developmental changes of the circadian system of the SCN. Transcription factors are required for the formation of neuropeptide-related neuronal networks. Although VIP is critical for synchrony of circadian rhythms in the neonatal SCN, it is not required for synchrony in the embryonic SCN. During postnatal development, the clock genes cryptochrome (Cry)1 and Cry2 are involved in the maturation of cellular networks, and AVP is involved in SCN networks. This mini-review focuses on the functional roles of neuropeptides in the SCN based on recent findings in the literature.

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