scholarly journals The tail of cryptochromes: an intrinsically disordered cog within the mammalian circadian clock

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Gian Carlo G. Parico ◽  
Carrie L. Partch
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Essential Role ◽  
Ubiquitin Ligases ◽  
Cry Proteins ◽  
Intrinsically Disordered ◽  
Homology Region ◽  
Terminal Domain ◽  
Evolutionarily Conserved ◽  
Necessary And Sufficient

AbstractCryptochrome (CRY) proteins play an essential role in regulating mammalian circadian rhythms. CRY is composed of a structured N-terminal domain known as the photolyase homology region (PHR), which is tethered to an intrinsically disordered C-terminal tail. The PHR domain is a critical hub for binding other circadian clock components such as CLOCK, BMAL1, PERIOD, or the ubiquitin ligases FBXL3 and FBXL21. While the isolated PHR domain is necessary and sufficient to generate circadian rhythms, removing or modifying the cryptochrome tails modulates the amplitude and/or periodicity of circadian rhythms, suggesting that they play important regulatory roles in the molecular circadian clock. In this commentary, we will discuss how recent studies of these intrinsically disordered tails are helping to establish a general and evolutionarily conserved model for CRY function, where the function of PHR domains is modulated by reversible interactions with their intrinsically disordered tails.

scholarly journals The essential role of cAMP/Ca2+ signalling in mammalian circadian timekeeping

2012 ◽  
Vol 40 (1) ◽  
pp. 44-50 ◽  
Author(s):  
John S. O'Neill ◽  
Akhilesh B. Reddy
Keyword(s):  
Circadian Rhythms ◽  
Suprachiasmatic Nucleus ◽  
Essential Role ◽  
Second Messenger ◽  
Feedback Loops ◽  
Intracellular Signalling ◽  
Molecular Models ◽  
Master Regulator ◽  
Necessary And Sufficient

Approximately daily, or circadian, rhythms are ubiquitous across eukaryotes. They are manifest in the temporal co-ordination of metabolism, physiology and behaviour, thereby allowing organisms to anticipate and synchronize with daily environmental cycles. Although cellular rhythms are self-sustained and cell-intrinsic, in mammals, the master regulator of timekeeping is localized within the hypothalamic SCN (suprachiasmatic nucleus). Molecular models for mammalian circadian rhythms have focused largely on transcriptional–translational feedback loops, but recent data have revealed essential contributions by intracellular signalling mechanisms. cAMP and Ca2+ signalling are not only regulated by the cellular clock, but also contribute directly to the timekeeping mechanism, in that appropriate manipulations determine the canonical pacemaker properties of amplitude, phase and period. It is proposed that daily auto-amplification of second messenger activity, through paracrine neuropeptidergic coupling, is necessary and sufficient to account for the increased amplitude, accuracy and robustness of SCN timekeeping.

scholarly journals EGCG binds intrinsically disordered N-terminal domain of p53 and disrupts p53-MDM2 interaction

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Zhao ◽  
Alan Blayney ◽  
Xiaorong Liu ◽  
Lauren Gandy ◽  
Weihua Jin ◽  
...  
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
Epigallocatechin Gallate ◽  
Cancer Drug ◽  
Dynamic Interactions ◽  
Cancer Drug Discovery ◽  
Intrinsically Disordered ◽  
Terminal Domain ◽  
Cancerous Cells

AbstractEpigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Using SPR and NMR, here we report a direct, μM interaction between EGCG and the tumor suppressor p53 (KD = 1.6 ± 1.4 μM), with the disordered N-terminal domain (NTD) identified as the major binding site (KD = 4 ± 2 μM). Large scale atomistic simulations (>100 μs), SAXS and AUC demonstrate that EGCG-NTD interaction is dynamic and EGCG causes the emergence of a subpopulation of compact bound conformations. The EGCG-p53 interaction disrupts p53 interaction with its regulatory E3 ligase MDM2 and inhibits ubiquitination of p53 by MDM2 in an in vitro ubiquitination assay, likely stabilizing p53 for anti-tumor activity. Our work provides insights into the mechanisms for EGCG’s anticancer activity and identifies p53 NTD as a target for cancer drug discovery through dynamic interactions with small molecules.

scholarly journals Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

2021 ◽  
Vol 22 (2) ◽  
pp. 676
Author(s):  
Andy W. C. Man ◽  
Huige Li ◽  
Ning Xia
Keyword(s):  
Circadian Rhythm ◽  
Cardiovascular Diseases ◽  
Circadian Rhythms ◽  
Circadian Clock ◽  
Therapeutic Target ◽  
Environmental Changes ◽  
Clock Genes ◽  
Vascular System ◽  
Peripheral Tissues ◽  
Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

scholarly journals The signal transducer gp130: Solution structure of the carboxy-terminal domain of the cytokine receptor homology region

2008 ◽  
Vol 8 (1) ◽  
pp. 5-12 ◽  
Author(s):  
Thomas Kernebeck ◽  
Stefan Pflanz ◽  
Peter C. Heinrich ◽  
Axel Wollmer ◽  
Joachim Grötzinger ◽  
...  
Keyword(s):  
Solution Structure ◽  
Cytokine Receptor ◽  
Signal Transducer ◽  
Homology Region ◽  
Terminal Domain ◽  
Carboxy Terminal Domain ◽  
Carboxy Terminal

scholarly journals Structural heterogeneity in the intrinsically disordered RNA polymerase II C-terminal domain

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Bede Portz ◽  
Feiyue Lu ◽  
Eric B. Gibbs ◽  
Joshua E. Mayfield ◽  
M. Rachel Mehaffey ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Structural Heterogeneity ◽  
Intrinsically Disordered ◽  
Terminal Domain

scholarly journals Improving the Performance of Simulations of the Intrinsically Disordered N-Terminal Domain from P53

2017 ◽  
Vol 112 (3) ◽  
pp. 207a-208a
Author(s):  
Nic A. Ezzell ◽  
Yue Zhang ◽  
Steven T. Whitten ◽  
Nicholas C. Fitzkee
Keyword(s):  
Intrinsically Disordered ◽  
Terminal Domain

scholarly journals Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation

2017 ◽  
Vol 28 (6) ◽  
pp. 834-842 ◽  
Author(s):  
Amol Chaudhari ◽  
Richa Gupta ◽  
Sonal Patel ◽  
Nikkhil Velingkaar ◽  
Roman Kondratov
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Skeletal Muscles ◽  
Cancer Metabolism ◽  
Reduced Body ◽  
Circadian Control ◽  
Cell Growth And Proliferation ◽  
Deficient Mice ◽  
Igf Signaling

Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is implicated in regulation of cancer, metabolism, and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through cryptochromes (CRYs)—transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted in Cry-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, Cry-deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 upon Cry deficiency correlates with reduced Igf-1 mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone–induced, JAK2 kinase–mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles of Cry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon Cry deficiency, which places CRY activity downstream from JAK2. Thus CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation, which provides the mechanism for circadian rhythms in IGF signaling in vivo.

Circadian clock precision, health, and longevity

2021 ◽  
Vol 23 (1) ◽  
pp. 3-15
Author(s):  
D. G. Gubin ◽  
◽  
S. N. Kolomeichuk ◽  
D. Weinert ◽  
◽  
...  
Keyword(s):  
Health Status ◽  
Circadian Rhythms ◽  
Life Expectancy ◽  
Circadian Clock ◽  
Animal Species ◽  
Genetic Factors ◽  
High Amplitude ◽  
Phenotypic Trait ◽  
Precision Health ◽  
Lower Morbidity

An accurate circadian clock, associated with the precise intrinsic period, tau, can be linked with a definite chronotype and health status. Exemplified by different animal species, and, as we argue herein, may as well be in humans, endogenous tau close enough to 24 hours is associated with higher life expectancy, lower morbidity, and is possibly adhered to moderate morning chronotype. Accurate circadian tau facilitates maintaining a high amplitude of circadian rhythms, a phenotypic trait that is related to health and longevity. Some genetic factors that coordinate tau and ensure circadian clock precision is considered.

PEPTIDE REGULATES HUMAN CIRCADIAN RHYTHMS GENES EXPRESSION DURING PINEAL GLAND ACCELERATED AGING

2020 ◽  
pp. 429-435
Author(s):  
О. М. Ивко ◽  
Н. С. Линькова ◽  
А. Р. Ильина ◽  
А. А. Шарова ◽  
Г. А. Рыжак
Keyword(s):  
Circadian Rhythms ◽  
Pineal Gland ◽  
Circadian Clock ◽  
Peripheral Blood ◽  
Accelerated Aging ◽  
Peripheral Blood Lymphocytes ◽  
Circadian Genes ◽  
Blood Lymphocytes ◽  
Aged People ◽  
Genes Expression

Ночная работа приводит к десинхронизации биоритмов, нарушению мелатонинобразующей функции и ускоренному старению эпифиза человека. Одним из перспективных геропротекторов, восстанавливающих синтез эпифизарного мелатонина, является пептид AEDG ( Ala-Glu-Asp-Gly ). Последний в 1,7 раза повышает экскрецию 6-сульфатоксимелатонина в моче людей среднего возраста, у которых этот показатель исходно снижен. Кроме того, у людей со сниженной мелатонинобразующей функцией эпифиза, пептид AEDG нормализует повышенную экспрессию циркадных генов Clock и Csnk 1 e в лейкоцитах и в 2 раза повышает сниженную экспрессию гена Cry 2 в лимфоцитах крови. В основе геропротекторного эффекта пептида AEDG лежит его способность восстанавливать мелатонинобразующую функцию эпифиза через регуляцию экспрессии часовых генов человека. Night work provides biorhythms desynchronization, disorder of melatonin-producing function and accelerated pineal gland aging. One of the promising geroprotectors restoring the pineal melatonin synthesis is the AEDG ( Ala-Glu-Asp-Gly ) peptide. AEDG peptide increases in 1,7 times the 6-sulfatoxymelatonin (6-SOMT) excretion in the urine of middle-aged people. Moreover, AEDG peptide normalized circadian Clock and Csnk1e genes hyper expression in leukocytes in 1,9-2,1 times and increases the Cry 2 gene hypo expression in peripheral blood lymphocytes in 2 times in people with reduced melatonin-producing epiphysis function. The geroprotective effect of the AEDG peptide is based on its ability to restore the epiphysis melatonin-producing function by means regulation of human circadian genes expression.

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