scholarly journals Post-translational Modifications are Required for Circadian Clock Regulation in Vertebrates

2019 ◽  
Vol 20 (5) ◽  
pp. 332-339 ◽  
Author(s):  
Yoshimi Okamoto-Uchida ◽  
Junko Izawa ◽  
Akari Nishimura ◽  
Atsuhiko Hattori ◽  
Nobuo Suzuki ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Feedback Loops ◽  
Circadian Clocks ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Negative Feedback Loops ◽  
Genetic Techniques ◽  
External Signals ◽  
Exact Timing

Circadian clocks are intrinsic, time-tracking systems that bestow upon organisms a survival advantage. Under natural conditions, organisms are trained to follow a 24-h cycle under environmental time cues such as light to maximize their physiological efficiency. The exact timing of this rhythm is established via cell-autonomous oscillators called cellular clocks, which are controlled by transcription/ translation-based negative feedback loops. Studies using cell-based systems and genetic techniques have identified the molecular mechanisms that establish and maintain cellular clocks. One such mechanism, known as post-translational modification, regulates several aspects of these cellular clock components, including their stability, subcellular localization, transcriptional activity, and interaction with other proteins and signaling pathways. In addition, these mechanisms contribute to the integration of external signals into the cellular clock machinery. Here, we describe the post-translational modifications of cellular clock regulators that regulate circadian clocks in vertebrates.

The Use of Chemical Compounds to Identify the Regulatory Mechanisms of Vertebrate Circadian Clocks

2020 ◽  
Vol 21 (5) ◽  
pp. 425-432
Author(s):  
Yoshimi Okamoto-Uchida ◽  
Akari Nishimura ◽  
Junko Izawa ◽  
Atsuhiko Hattori ◽  
Nobuo Suzuki ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Chemical Compounds ◽  
Stability Control ◽  
Circadian Clocks ◽  
Light Signaling ◽  
Negative Feedback Loops ◽  
Exact Timing

Circadian clocks are intrinsic, time-tracking processes that confer a survival advantage on an organism. Under natural conditions, they follow approximately a 24-h day, modulated by environmental time cues, such as light, to maximize an organism’s physiological efficiency. The exact timing of this rhythm is established by cell-autonomous oscillators called cellular clocks, which are controlled by transcription–translation negative feedback loops. Studies of cell-based systems and wholeanimal models have utilized a pharmacological approach in which chemical compounds are used to identify molecular mechanisms capable of establishing and maintaining cellular clocks, such as posttranslational modifications of cellular clock regulators, chromatin remodeling of cellular clock target genes’ promoters, and stability control of cellular clock components. In addition, studies with chemical compounds have contributed to the characterization of light-signaling pathways and their impact on the cellular clock. Here, the use of chemical compounds to study the molecular, cellular, and behavioral aspects of the vertebrate circadian clock system is described.

scholarly journals C-terminal tail polyglycylation and polyglutamylation alter microtubule mechanical properties

2019 ◽  
Author(s):  
Kathryn P. Wall ◽  
Harold Hart ◽  
Thomas Lee ◽  
Cynthia Page ◽  
Taviare L. Hawkins ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Molecular Mechanisms ◽  
High Stress ◽  
Resonance Spectroscopy ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Peptide Backbone ◽  
Post Translational Modifications ◽  
Intrinsic Stiffness ◽  
Insight Into

ABSTRACTMicrotubules are biopolymers that perform diverse cellular functions. The regulation of microtubule behavior occurs in part through post-translational modification of both the α- and β- subunits of tubulin. One class of modifications is the heterogeneous addition of glycine and glutamate residues to the disordered C-terminal tails of tubulin. Due to their prevalence in stable, high stress cellular structures such as cilia, we sought to determine if these modifications alter the intrinsic stiffness of microtubules. Here we describe the purification and characterization of differentially-modified pools of tubulin from Tetrahymena thermophila. We found that glycylation on the α-C-terminal tail is a key determinant of microtubule stiffness, but does not affect the number of protofilaments incorporated into microtubules. We measured the dynamics of the tail peptide backbone using nuclear magnetic resonance spectroscopy. We found that the spin-spin relaxation rate (R2) showed a pronounced decreased as a function of distance from the tubulin surface for the α-tubulin tail, indicating that the α-tubulin tail interacts with the dimer surface. This suggests that the interactions of the α-C-terminal tail with the tubulin body contributes to the stiffness of the assembled microtubule, providing insight into the mechanism by which glycylation and glutamylation can alter microtubule mechanical properties.SIGNIFICANCEMicrotubules are regulated in part by post-translational modifications including the heterogeneous addition of glycine and glutamate residues to the C-terminal tails. By producing and characterizing differentially-modified tubulin, this work provides insight into the molecular mechanisms of how these modifications alter intrinsic microtubule properties such as flexibility. These results have broader implications for mechanisms of how ciliary structures are able to function under high stress.

scholarly journals Reading More than Histones: The Prevalence of Nucleic Acid Binding among Reader Domains

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2614 ◽  
Author(s):  
Tyler Weaver ◽  
Emma Morrison ◽  
Catherine Musselman
Keyword(s):  
Nucleic Acid ◽  
Molecular Mechanisms ◽  
Binding Activity ◽  
Nucleic Acid Binding ◽  
Post Translational Modification ◽  
Histone Proteins ◽  
Post Translational Modifications ◽  
Histone Binding ◽  
Functional Implications ◽  
Nucleic Acid Binding Activity

The eukaryotic genome is packaged into the cell nucleus in the form of chromatin, a complex of genomic DNA and histone proteins. Chromatin structure regulation is critical for all DNA templated processes and involves, among many things, extensive post-translational modification of the histone proteins. These modifications can be “read out” by histone binding subdomains known as histone reader domains. A large number of reader domains have been identified and found to selectively recognize an array of histone post-translational modifications in order to target, retain, or regulate chromatin-modifying and remodeling complexes at their substrates. Interestingly, an increasing number of these histone reader domains are being identified as also harboring nucleic acid binding activity. In this review, we present a summary of the histone reader domains currently known to bind nucleic acids, with a focus on the molecular mechanisms of binding and the interplay between DNA and histone recognition. Additionally, we highlight the functional implications of nucleic acid binding in chromatin association and regulation. We propose that nucleic acid binding is as functionally important as histone binding, and that a significant portion of the as yet untested reader domains will emerge to have nucleic acid binding capabilities.

scholarly journals Phosphorylation and Ubiquitylation Regulate Protein Trafficking, Signaling, and the Biogenesis of Primary Cilia

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena A. May ◽  
Tommy J. Sroka ◽  
David U. Mick
Keyword(s):  
Protein Trafficking ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
Post Translational Modifications ◽  
Quiescent Cells ◽  
Cellular Environment ◽  
Regulate Protein ◽  
Cycle Dependent ◽  
External Signals ◽  
Signaling Components

The primary cilium is a solitary, microtubule-based membrane protrusion extending from the surface of quiescent cells that senses the cellular environment and triggers specific cellular responses. The functions of primary cilia require not only numerous different components but also their regulated interplay. The cilium performs highly dynamic processes, such as cell cycle-dependent assembly and disassembly as well as delivery, modification, and removal of signaling components to perceive and process external signals. On a molecular level, these processes often rely on a stringent control of key modulatory proteins, of which the activity, localization, and stability are regulated by post-translational modifications (PTMs). While an increasing number of PTMs on ciliary components are being revealed, our knowledge on the identity of the modifying enzymes and their modulation is still limited. Here, we highlight recent findings on cilia-specific phosphorylation and ubiquitylation events. Shedding new light onto the molecular mechanisms that regulate the sensitive equilibrium required to maintain and remodel primary cilia functions, we discuss their implications for cilia biogenesis, protein trafficking, and cilia signaling processes.

scholarly journals The Roles of Post-Translational Modifications in STAT3 Biological Activities and Functions

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 956
Author(s):  
Annachiara Tesoriere ◽  
Alberto Dinarello ◽  
Francesco Argenton
Keyword(s):  
Transcription Factor ◽  
Cancer Progression ◽  
Transcriptional Activity ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Cellular Models ◽  
Stat3 Phosphorylation ◽  
Cellular Context ◽  
Cell Growth And Proliferation

STAT3 is an important transcription factor that regulates cell growth and proliferation by regulating gene transcription of a plethora of genes. This protein also has many roles in cancer progression and several tumors such as prostate, lung, breast, and intestine cancers that are characterized by strong STAT3-dependent transcriptional activity. This protein is post-translationally modified in different ways according to cellular context and stimulus, and the same post-translational modification can have opposite effects in different cellular models. In this review, we describe the studies performed on the main modifications affecting the activity of STAT3: phosphorylation of tyrosine 705 and serine 727; acetylation of lysine 49, 87, 601, 615, 631, 685, 707, and 709; and methylation of lysine 49, 140, and 180. The extensive results obtained by different studies demonstrate that post-translational modifications drastically change STAT3 activities and that we need further analysis to properly elucidate all the functions of this multifaceted transcription factor.

scholarly journals SDC mediates DNA methylation-controlled clock pace by interacting with ZTL in Arabidopsis

2021 ◽  
Vol 49 (7) ◽  
pp. 3764-3780
Author(s):  
Wenwen Tian ◽  
Ruyi Wang ◽  
Cunpei Bo ◽  
Yingjun Yu ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Dna Methyltransferases ◽  
Feedback Loops ◽  
Circadian Clocks ◽  
Fine Tuning ◽  
Dna Hypomethylation ◽  
Proteolytic Cascade ◽  
Molecular Bases

Abstract Molecular bases of eukaryotic circadian clocks mainly rely on transcriptional-translational feedback loops (TTFLs), while epigenetic codes also play critical roles in fine-tuning circadian rhythms. However, unlike histone modification codes that play extensive and well-known roles in the regulation of circadian clocks, whether DNA methylation (5mC) can affect the circadian clock, and the associated underlying molecular mechanisms, remains largely unexplored in many organisms. Here we demonstrate that global genome DNA hypomethylation can significantly lengthen the circadian period of Arabidopsis. Transcriptomic and genetic evidence demonstrate that SUPPRESSOR OF drm1 drm2 cmt3 (SDC), encoding an F-box containing protein, is required for the DNA hypomethylation-tuned circadian clock. Moreover, SDC can physically interact with another F-box containing protein ZEITLUPE (ZTL) to diminish its accumulation. Genetic analysis further revealed that ZTL and its substrate TIMING OF CAB EXPRESSION 1 (TOC1) likely act downstream of DNA methyltransferases to control circadian rhythm. Together, our findings support the notion that DNA methylation is important to maintain proper circadian pace in Arabidopsis, and further established that SDC links DNA hypomethylation with a proteolytic cascade to assist in tuning the circadian clock.

scholarly journals Switching between apparently redundant iron-uptake mechanisms benefits bacteria in changeable environments

2013 ◽  
Vol 280 (1764) ◽  
pp. 20131055 ◽  
Author(s):  
Zoé Dumas ◽  
Adin Ross-Gillespie ◽  
Rolf Kümmerli
Keyword(s):  
Iron Uptake ◽  
Molecular Mechanisms ◽  
Feedback Loops ◽  
Iron Limitation ◽  
Collective Decision Making ◽  
Group Level ◽  
Negative Feedback Loops ◽  
Positive And Negative Feedback ◽  
Vital Resource ◽  
Better Than

Bacteria often possess multiple siderophore-based iron uptake systems for scavenging this vital resource from their environment. However, some siderophores seem redundant, because they have limited iron-binding efficiency and are seldom expressed under iron limitation. Here, we investigate the conundrum of why selection does not eliminate this apparent redundancy. We focus on Pseudomonas aeruginosa , a bacterium that can produce two siderophores—the highly efficient but metabolically expensive pyoverdine, and the inefficient but metabolically cheap pyochelin. We found that the bacteria possess molecular mechanisms to phenotypically switch from mainly producing pyoverdine under severe iron limitation to mainly producing pyochelin when iron is only moderately limited. We further show that strains exclusively producing pyochelin grew significantly better than strains exclusively producing pyoverdine under moderate iron limitation, whereas the inverse was seen under severe iron limitation. This suggests that pyochelin is not redundant, but that switching between siderophore strategies might be beneficial to trade off efficiencies versus costs of siderophores. Indeed, simulations parameterized from our data confirmed that strains retaining the capacity to switch between siderophores significantly outcompeted strains defective for one or the other siderophore under fluctuating iron availabilities. Finally, we discuss how siderophore switching can be viewed as a form of collective decision-making, whereby a coordinated shift in behaviour at the group level emerges as a result of positive and negative feedback loops operating among individuals at the local scale.

scholarly journals Oxygen-dependent changes in HIF binding partners and post-translational modifications regulate stability and transcriptional activity

2020 ◽  
Author(s):  
Leonard Daly ◽  
Philip J. Brownridge ◽  
Violaine Sée ◽  
Claire E. Eyers
Keyword(s):  
Transcriptional Activity ◽  
Evolutionary Analysis ◽  
Post Translational Modification ◽  
Low Oxygen ◽  
Post Translational Modifications ◽  
Functional Roles ◽  
Binding Partners ◽  
Associated Proteins ◽  
The Stability

AbstractAdaption of cells to low oxygen environments is an essential process mediated in part by the Hypoxia Inducible Factors (HIFs). Like other transcription factors, the stability and transcriptional activity of HIFs, and consequently the hypoxic response, are regulated by post-translational modification (PTM) and changes in biomolecular interactions. However, our current understanding of PTM-mediated regulation of HIFs is primarily based on in vitro protein fragment-based studies, with validation typically having been conducted by in cellulo fragment expression and hypoxia mimicking drugs. Consequently, we still lack an understanding of true oxygen deprivation signaling via HIFα. Using an immunoprecipitation-based, mass spectrometry approach, we characterize the regulation of in cellulo expressed full-length HIF-1α and HIF-2α, in terms of both PTM and binding partners, in response to normoxia (21% oxygen) and hypoxia (1% oxygen). These studies revealed that a change in oxygen tension significantly alters the complexity and composition of HIF-α protein interaction networks, with HIF-2α in particular having an extended hypoxia-induced interactome, most notably with mitochondrial-associated proteins. Both HIFα isoforms are heavily covalently modified: we define ~40 different sites of PTM on each of HIF-1α and HIF-2α, comprising 13 different PTM types, including multiple cysteine modifications and a highly unusual phosphocysteine. Over 80% of the PTMs identified are novel, and approximately half exhibit oxygen-dependency under these conditions. Combined with domain and evolutionary analysis of >225 vertebrate species, we validate Ser31 phosphorylation on HIF-1α as a regulator of transcription, and propose functional roles for Thr406, Thr528 and Ser581 on HIF-2α.

scholarly journals Coupling protocol of interlocked feedback oscillators in circadian clocks

2020 ◽  
Vol 17 (167) ◽  
pp. 20200287
Author(s):  
Md. Mamunur Rashid ◽  
Hiroyuki Kurata
Keyword(s):  
Coupled Oscillators ◽  
Random Parameter ◽  
Feedback Loops ◽  
Circadian Clocks ◽  
Negative Feedback Loops ◽  
Phase Cycle ◽  
Parameter Perturbations ◽  
Coupling Parameters ◽  
Coupling Time ◽  
Master Clock

Circadian rhythms (approx. 24 h) show the robustness of key oscillatory features such as phase, period and amplitude against external and internal variations. The robustness of Drosophila circadian clocks can be generated by interlocked transcriptional–translational feedback loops, where two negative feedback loops are coupled through mutual activations. The mechanisms by which such coupling protocols have survived out of many possible protocols remain to be revealed. To address this question, we investigated two distinct coupling protocols: activator-coupled oscillators (ACO) and repressor-coupled oscillators (RCO). We focused on the two coupling parameters: coupling dissociation constant and coupling time-delay. Interestingly, the ACO was able to produce anti-phase or morning–evening cycles, whereas the RCO produced in-phase ones. Deterministic and stochastic analyses demonstrated that the anti-phase ACO provided greater fluctuations in amplitude not only with respect to changes in coupling parameters but also to random parameter perturbations than the in-phase RCO. Moreover, the ACO deteriorated the entrainability to the day–night master clock, whereas the RCO produced high entrainability. Considering that the real, interlocked feedback loops have evolved as the ACO, instead of the RCO, we first proposed a hypothesis that the morning–evening or anti-phase cycle is more essential for Drosophila than achieving robustness and entrainability.

scholarly journals Intersection of Redox Chemistry and Ubiquitylation: Post-Translational Modifications Required for Maintaining Cellular Homeostasis and Neuroprotection

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2121
Author(s):  
Emma I. Kane ◽  
Kelly L. Waters ◽  
Donald E. Spratt
Keyword(s):  
Molecular Mechanisms ◽  
Ubiquitin Proteasome System ◽  
Post Translational Modification ◽  
Ubiquitin Chain ◽  
Post Translational Modifications ◽  
Specific Attachment ◽  
Ubiquitin Proteasome ◽  
Cellular Pathways ◽  
Intracellular Fate ◽  
Chain Type

Neurodegeneration has been predominantly recognized as neuronal breakdown induced by the accumulation of aggregated and/or misfolded proteins and remains a preliminary factor in age-dependent disease. Recently, critical regulating molecular mechanisms and cellular pathways have been shown to induce neurodegeneration long before aggregate accumulation could occur. Although this opens the possibility of identifying biomarkers for early onset diagnosis, many of these pathways vary in their modes of dysfunction while presenting similar clinical phenotypes. With selectivity remaining difficult, it is promising that these neuroprotective pathways are regulated through the ubiquitin-proteasome system (UPS). This essential post-translational modification (PTM) involves the specific attachment of ubiquitin onto a substrate, specifically marking the ubiquitin-tagged protein for its intracellular fate based upon the site of attachment, the ubiquitin chain type built, and isopeptide linkages between different ubiquitin moieties. This review highlights both the direct and indirect impact ubiquitylation has in oxidative stress response and neuroprotection, and how irregularities in these intricate processes lead towards the onset of neurodegenerative disease (NDD).

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