scholarly journals Modulation of conformational equilibrium by phosphorylation underlies the activation of deubiquitinase A

2020 ◽  
Vol 295 (12) ◽  
pp. 3945-3951 ◽  
Author(s):  
Ashish Kabra ◽  
Efsita Rumpa ◽  
Ying Li
Keyword(s):  
Conformational Equilibrium ◽  
Dynamic Properties ◽  
Conformational Dynamics ◽  
Negative Regulator ◽  
Type I ◽  
Serine Residue ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Catalytic Rate Constant ◽  
Conformational Properties

Deubiquitinases deconjugate ubiquitin modifications from target proteins and are involved in many cellular processes in eukaryotes. The functions of deubiquitinases are regulated by post-translational modifications, mainly phosphorylation and ubiquitination. Post-translational modifications can result in subtle changes in structural and dynamic properties, which are difficult to identify but functionally important. In this work, we used NMR spectroscopy to characterize the conformational properties of the human deubiquitinase A (DUBA), a negative regulator of type I interferon. DUBA activity is regulated by phosphorylation at a single serine residue, Ser-177. We found that the catalytic rate constant of DUBA is enhanced by phosphorylation. By comparing NMR and enzyme kinetics data among different forms of DUBA with low and high activities, we concluded that a two-state equilibrium that was present only in phosphorylated DUBA is important for DUBA activity. Our results highlight the importance of defining conformational dynamics in understanding the mechanism of DUBA activation.

scholarly journals Novel Roles for the Sirtuin Deacylase SIRT5 in Normal Physiology and in Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 741-741
Author(s):  
David Lombard
Keyword(s):  
Mitochondrial Matrix ◽  
Genomic Integrity ◽  
Biological Functions ◽  
Protein Targets ◽  
Post Translational Modifications ◽  
Catalytic Activities ◽  
Cellular Processes ◽  
Specific Cancer ◽  
Cancer Types ◽  
Chromatin Biology

Abstract Sirtuins are NAD+-dependent deacylases that regulate diverse cellular processes such as metabolic homeostasis and genomic integrity. Mammals possess seven sirtuin family members, SIRT1-SIRT7, that display diverse subcellular localization patterns, catalytic activities, protein targets, and biological functions. Three sirtuins, SIRT3, SIRT4, and SIRT5, are primarily located in the mitochondrial matrix. SIRT5 is a very inefficient deacetylase, instead removing negatively charged post-translational modifications (succinyl, glutaryl, and malonyl groups) from lysines of its target proteins, in mitochondria and throughout the cell. SIRT5 plays only modest known roles in normal physiology, with its major functions occurring in the heart under stress conditions. In contrast, in specific cancer types, including melanoma, we have identified a major pro-survival role for SIRT5. We have traced this function of SIRT5 to novel roles for this protein in regulating chromatin biology. New insights into mechanisms of SIRT5 action in cancer, and in normal myocardium, will be discussed.

scholarly journals N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weinan Qiu ◽  
Qingyang Zhang ◽  
Rui Zhang ◽  
Yangxu Lu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Rna Virus ◽  
Negative Regulator ◽  
Rna Modification ◽  
Type I ◽  
Viral Immunity ◽  
Potential Therapeutic Target ◽  
Viral Dsrna ◽  
Double Stranded Rna ◽  
Genetic Ablation ◽  
Vesicular Stomatitis

AbstractDouble-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N6-methyladenosine (m6A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 translocates into the cytoplasm to increase m6A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m6A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity.

scholarly journals TFEB Signalling-Related MicroRNAs and Autophagy

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 985
Author(s):  
Davide Corà ◽  
Federico Bussolino ◽  
Gabriella Doronzo
Keyword(s):  
Transcriptional Regulation ◽  
Stress Factors ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Factor Deficiency ◽  
Transcription Factor Eb ◽  
Important Regulator ◽  
Response To Stress ◽  
Post Transcriptional Regulation

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.

Trabecular Bone is Increased in a Rat Model of Polycystic Ovary Syndrome

2020 ◽  
Author(s):  
Lady Katerine Serrano Mujica ◽  
Werner Giehl Glanzner ◽  
Amanda Luiza Prante ◽  
Vitor Braga Rissi ◽  
Gabrielle Rebeca Everling Correa ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Bone Formation ◽  
Type I Collagen ◽  
Polycystic Ovary ◽  
Osteoclast Differentiation ◽  
Bone Volume ◽  
Negative Regulator ◽  
Type I ◽  
Ovary Syndrome ◽  
The Impact

AbstractPolycystic ovary syndrome (PCOS) in an intricate disorder characterized by reproductive and metabolic abnormalities that may affect bone quality and strength along with the lifespan. The present study analysed the impact of postnatal androgenization (of a single dose of testosterone propionate 1.25 mg subcutaneously at day 5 of life) on bone development and markers of bone metabolism in adult female Wistar rats. Compared with healthy controls, the results of measurements of micro-computed tomography (microCT) of the distal femur of androgenized rats indicated an increased cortical bone volume voxel bone volume to total volume (VOX BV/TV) and higher trabecular number (Tb.n) with reduced trabecular separation (Tb.sp). A large magnitude effect size was observed in the levels of circulating bone formation Procollagen I N-terminal propeptide (P1NP) at day 60 of life; reabsorption cross-linked C-telopeptide of type I collagen (CTX) markers were similar between the androgenized and control rats at days 60 and 110 of life. The analysis of gene expression in bone indicated elements for an increased bone mass such as the reduction of the Dickkopf-1 factor (Dkk1) a negative regulator of osteoblast differentiation (bone formation) and the reduction of Interleukin 1-b (Il1b), an activator of osteoclast differentiation (bone reabsorption). Results from this study highlight the possible role of the developmental programming on bone microarchitecture with reference to young women with PCOS.

Molecular Origins of the Unique Conformational Properties of the Polysilanes: A Molecular Dynamics Study of Poly(Di-N-Hexylsilane)

1992 ◽  
Vol 278 ◽  
Author(s):  
William J. Welsh ◽  
Samuel H. Tersigni ◽  
Wangkan Lin
Keyword(s):  
Molecular Dynamics ◽  
Torsion Angle ◽  
Model Compound ◽  
Energy Surface ◽  
Conformational Dynamics ◽  
Conformational Transitions ◽  
Torsion Angles ◽  
Global Energy Minimum ◽  
Conformational Properties ◽  
Backbone Torsion Angle

AbstractThe conformational dynamics of a model compound for poly(di-n-hexylsilane) (PDHS) has been explored using the new molecular dynamics program MM3-MD. MM3-MD trajectories at variable temperatures reveal two abrupt conformational transitions, one near -182°C and another near -175°C, associated with two energy barriers on the potential-energy surface. The first transition near -182°C allows shifts in the backbone torsion angle from that defined by the global energy minimum designated off-trans to that corresponding to a statistical collection of torsion angles within the range trans ±30°. The second transition near -175°C allows the backbone torsion angle to explore the remainder of its torsional space. The sidechain dynamics follows a similar pattern. We suggest that the abrupt transition calculated here at -182°C for “gas.phase” PDHS corresponds to that observed for PDHS at -28°C in solution and at 42°C in the solid state.

The nucleosome: a little variation goes a long wayThis paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

2006 ◽  
Vol 84 (4) ◽  
pp. 505-507 ◽  
Author(s):  
Emily Bernstein ◽  
Sandra B. Hake
Keyword(s):  
Peer Review Process ◽  
Gene Activation ◽  
Epigenetic Inheritance ◽  
Histone Variants ◽  
Post Translational Modifications ◽  
Chromatin Compaction ◽  
Cellular Processes ◽  
Chromatin Template ◽  
Mitosis And Meiosis ◽  
Selection Of

Changes in the overall structure of chromatin are essential for the proper regulation of cellular processes, including gene activation and silencing, DNA repair, chromosome segregation during mitosis and meiosis, X chromosome inactivation in female mammals, and chromatin compaction during apoptosis. Such alterations of the chromatin template occur through at least 3 interrelated mechanisms: post-translational modifications of histones, ATP-dependent chromatin remodeling, and the incorporation (or replacement) of specialized histone variants into chromatin. Of these mechanisms, the exchange of variants into and out of chromatin is the least well understood. However, the exchange of conventional histones for variant histones has distinct and profound consequences within the cell. This review focuses on the growing number of mammalian histone variants, their particular biological functions and unique features, and how they may affect the structure of the nucleosome. We propose that a given nucleosome might not consist of heterotypic variants, but rather, that only specific histone variants come together to form a homotypic nucleosome, a hypothesis that we refer to as the nucleosome code. Such nucleosomes might in turn participate in marking specific chromatin domains that may contribute to epigenetic inheritance.

scholarly journals eIF2 interactions with initiator tRNA and eIF2B are regulated by post-translational modifications and conformational dynamics

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Victoria Beilsten-Edmands ◽  
Yuliya Gordiyenko ◽  
Jocky CK Kung ◽  
Shabaz Mohammed ◽  
Carla Schmidt ◽  
...  
Keyword(s):  
Conformational Dynamics ◽  
Post Translational Modifications ◽  
Initiator Trna

scholarly journals MAVS: A Two-Sided CARD Mediating Antiviral Innate Immune Signaling and Regulating Immune Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunqiang Chen ◽  
Yuheng Shi ◽  
Jing Wu ◽  
Nan Qi
Keyword(s):  
Signal Transduction ◽  
Innate Immune ◽  
Immune Homeostasis ◽  
Type I ◽  
Interferon Signaling ◽  
Immune Signaling ◽  
Post Translational Modifications ◽  
Innate Immune Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Mitochondrial antiviral signaling protein (MAVS) functions as a “switch” in the immune signal transduction against most RNA viruses. Upon viral infection, MAVS forms prion-like aggregates by receiving the cytosolic RNA sensor retinoic acid-inducible gene I-activated signaling and further activates/switches on the type I interferon signaling. While under resting state, MAVS is prevented from spontaneously aggregating to switch off the signal transduction and maintain immune homeostasis. Due to the dual role in antiviral signal transduction and immune homeostasis, MAVS has emerged as the central regulation target by both viruses and hosts. Recently, researchers show increasing interest in viral evasion strategies and immune homeostasis regulations targeting MAVS, especially focusing on the post-translational modifications of MAVS, such as ubiquitination and phosphorylation. This review summarizes the regulations of MAVS in antiviral innate immune signaling transduction and immune homeostasis maintenance.

scholarly journals Interplay between ADP-ribosyltransferases and essential cell signaling pathways controls cellular responses

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Flurina Boehi ◽  
Patrick Manetsch ◽  
Michael O. Hottiger
Keyword(s):  
Cell Signaling ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Cellular Responses ◽  
Dynamic Regulation ◽  
Post Translational Modifications ◽  
Adp Ribosylation ◽  
Cellular Processes ◽  
Adp Ribosyltransferase ◽  
Cell Signaling Pathways

AbstractSignaling cascades provide integrative and interactive frameworks that allow the cell to respond to signals from its environment and/or from within the cell itself. The dynamic regulation of mammalian cell signaling pathways is often modulated by cascades of protein post-translational modifications (PTMs). ADP-ribosylation is a PTM that is catalyzed by ADP-ribosyltransferases and manifests as mono- (MARylation) or poly- (PARylation) ADP-ribosylation depending on the addition of one or multiple ADP-ribose units to protein substrates. ADP-ribosylation has recently emerged as an important cell regulator that impacts a plethora of cellular processes, including many intracellular signaling events. Here, we provide an overview of the interplay between the intracellular diphtheria toxin-like ADP-ribosyltransferase (ARTD) family members and five selected signaling pathways (including NF-κB, JAK/STAT, Wnt-β-catenin, MAPK, PI3K/AKT), which are frequently described to control or to be controlled by ADP-ribosyltransferases and how these interactions impact the cellular responses.

scholarly journals DNA sequence is a major determinant of tetrasome dynamics

2019 ◽  
Author(s):  
O. Ordu ◽  
A. Lusser ◽  
N. H. Dekker
Keyword(s):  
Dna Sequence ◽  
Dna Sequences ◽  
Dynamic Properties ◽  
Conformational Dynamics ◽  
Magnetic Tweezers ◽  
Torsional Stress ◽  
High Affinity ◽  
Canonical State ◽  
Left And Right ◽  
Dna Wrapping

ABSTRACTEukaryotic genomes are hierarchically organized into protein-DNA assemblies for compaction into the nucleus. Nucleosomes, with the (H3-H4)2 tetrasome as a likely intermediate, are highly dynamic in nature by way of several different mechanisms. We have recently shown that tetrasomes spontaneously change the direction of their DNA wrapping between left- and right-handed conformations, which may prevent torque build-up in chromatin during active transcription or replication. DNA sequence has been shown to strongly affect nucleosome positioning throughout chromatin. It is not known, however, whether DNA sequence also impacts the dynamic properties of tetrasomes. To address this question, we examined tetrasomes assembled on a high-affinity DNA sequence using freely orbiting magnetic tweezers. In this context, we also studied the effects of mono- and divalent salts on the flipping dynamics. We found that neither DNA sequence nor altered buffer conditions affect overall tetrasome structure. In contrast, tetrasomes bound to high-affinity DNA sequences showed significantly altered flipping kinetics, predominantly via a reduction in the lifetime of the canonical state of left-handed wrapping. Increased mono- and divalent salt concentrations counteracted this behaviour. Thus, our study indicates that high-affinity DNA sequences impact not only the positioning of the nucleosome, but that they also endow the subnucleosomal tetrasome with enhanced conformational plasticity. This may provide a means to prevent histone loss upon exposure to torsional stress, thereby contributing to the integrity of chromatin at high-affinity sites.STATEMENT OF SIGNIFICANCECanonical (H3-H4)2 tetrasomes possess high conformational flexibility, as evidenced by their spontaneous flipping between states of left- and right-handed DNA wrapping. Here, we show that these conformational dynamics of tetrasomes cannot be described by a fixed set of rates over all conditions. Instead, an accurate description of their behavior must take into account details of their loading, in particular the underlying DNA sequence. In vivo, differences in tetrasome flexibility could be regulated by modifications of the histone core or the tetrasomal DNA, and as such constitute an intriguing, potentially adjustable mechanism for chromatin to accommodate the torsional stress generated by processes such as transcription and replication.

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