scholarly journals The Interactome of the Glucocorticoid Receptor and Its Influence on the Actions of Glucocorticoids in Combatting Inflammatory and Infectious Diseases

2016 ◽  
Vol 80 (2) ◽  
pp. 495-522 ◽  
Author(s):  
Ioanna Petta ◽  
Lien Dejager ◽  
Marlies Ballegeer ◽  
Sam Lievens ◽  
Jan Tavernier ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Nuclear Receptors ◽  
Protein Interactions ◽  
State Of The Art ◽  
Protein Protein Interactions ◽  
First Line ◽  
Microbial Diseases ◽  
The Family ◽  
Anti Inflammatory ◽  
First Line Treatment

SUMMARYGlucocorticoids (GCs) have been widely used for decades as a first-line treatment for inflammatory and autoimmune diseases. However, their use is often hampered by the onset of adverse effects or resistance. GCs mediate their effects via binding to glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. An important aspect of GR's actions, including its anti-inflammatory capacity, involves its interactions with various proteins, such as transcription factors, cofactors, and modifying enzymes, which codetermine receptor functionality. In this review, we provide a state-of-the-art overview of the protein-protein interactions (PPIs) of GR that positively or negatively affect its anti-inflammatory properties, along with mechanistic insights, if known. Emphasis is placed on the interactions that affect its anti-inflammatory effects in the presence of inflammatory and microbial diseases.

scholarly journals Anti-inflammatory functions of the glucocorticoid receptor require DNA binding

2020 ◽  
Vol 48 (15) ◽  
pp. 8393-8407
Author(s):  
Laura Escoter-Torres ◽  
Franziska Greulich ◽  
Fabiana Quagliarini ◽  
Michael Wierer ◽  
Nina Henriette Uhlenhaut
Keyword(s):  
Dna Binding ◽  
Glucocorticoid Receptor ◽  
Protein Interactions ◽  
Transcriptional Activation ◽  
Drug Target ◽  
Immunosuppressive Drug ◽  
Rna Seq ◽  
Protein Protein Interactions ◽  
Inflammatory Conditions ◽  
Anti Inflammatory

Abstract The glucocorticoid receptor is an important immunosuppressive drug target and metabolic regulator that acts as a ligand-gated transcription factor. Generally, GR’s anti-inflammatory effects are attributed to the silencing of inflammatory genes, while its adverse effects are ascribed to the upregulation of metabolic targets. GR binding directly to DNA is proposed to activate, whereas GR tethering to pro-inflammatory transcription factors is thought to repress transcription. Using mice with a point mutation in GR’s zinc finger, that still tether via protein–protein interactions while being unable to recognize DNA, we demonstrate that DNA binding is essential for both transcriptional activation and repression. Performing ChIP-Seq, RNA-Seq and proteomics under inflammatory conditions, we show that DNA recognition is required for the assembly of a functional co-regulator complex to mediate glucocorticoid responses. Our findings may contribute to the development of safer immunomodulators with fewer side effects.

scholarly journals Glycyrrhizic Acid for COVID-19: Findings of Targeting Pivotal Inflammatory Pathways Triggered by SARS-CoV-2

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjiang Zheng ◽  
Xiufang Huang ◽  
Yanni Lai ◽  
Xiaohong Liu ◽  
Yong Jiang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Interactions ◽  
Glycyrrhizic Acid ◽  
Enrichment Analysis ◽  
Host Factors ◽  
Pathway Enrichment Analysis ◽  
Protein Protein Interactions ◽  
Health Crisis ◽  
Inflammatory Pathways ◽  
Anti Inflammatory

Background: Coronavirus disease 2019 (COVID-19) is now a worldwide public health crisis. The causative pathogen is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Novel therapeutic agents are desperately needed. Because of the frequent mutations in the virus and its ability to cause cytokine storms, targeting the viral proteins has some drawbacks. Targeting cellular factors or pivotal inflammatory pathways triggered by SARS-CoV-2 may produce a broader range of therapies. Glycyrrhizic acid (GA) might be beneficial against SARS-CoV-2 because of its anti-inflammatory and antiviral characteristics and possible ability to regulate crucial host factors. However, the mechanism underlying how GA regulates host factors remains to be determined.Methods: In our report, we conducted a bioinformatics analysis to identify possible GA targets, biological functions, protein-protein interactions, transcription-factor-gene interactions, transcription-factor-miRNA coregulatory networks, and the signaling pathways of GA against COVID-19.Results: Protein-protein interactions and network analysis showed that ICAM1, MMP9, TLR2, and SOCS3 had higher degree values, which may be key targets of GA for COVID-19. GO analysis indicated that the response to reactive oxygen species was significantly enriched. Pathway enrichment analysis showed that the IL-17, IL-6, TNF-α, IFN signals, complement system, and growth factor receptor signaling are the main pathways. The interactions of TF genes and miRNA with common targets and the activity of TFs were also recognized.Conclusions: GA may inhibit COVID-19 through its anti-oxidant, anti-viral, and anti-inflammatory effects, and its ability to activate the immune system, and targeted therapy for those pathways is a predominant strategy to inhibit the cytokine storms triggered by SARS-CoV-2 infection.

scholarly journals A Specificity and Targeting Subunit of a Human SWI/SNF Family-Related Chromatin-Remodeling Complex

2000 ◽  
Vol 20 (23) ◽  
pp. 8879-8888 ◽  
Author(s):  
Zuqin Nie ◽  
Yutong Xue ◽  
Dafeng Yang ◽  
Sharleen Zhou ◽  
Bonnie J. Deroo ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Chromatin Remodeling ◽  
Protein Interactions ◽  
Transcriptional Activation ◽  
Gene Activation ◽  
Dna Interaction ◽  
Protein Protein Interactions ◽  
Baf Complex ◽  
Chromatin Remodeling Complexes

ABSTRACT The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. This family includes BAF (also called hSWI/SNF-A) and PBAF (hSWI/SNF-B) from humans and SWI/SNF and Rsc fromSaccharomyces cerevisiae. However, the relationship between the human and yeast complexes is unclear because all human subunits published to date are similar to those of both yeast SWI/SNF and Rsc. Also, the two human complexes have many identical subunits, making it difficult to distinguish their structures or functions. Here we describe the cloning and characterization of BAF250, a subunit present in human BAF but not PBAF. BAF250 contains structural motifs conserved in yeast SWI1 but not in any Rsc components, suggesting that BAF is related to SWI/SNF. BAF250 is also a homolog of the Drosophila melanogaster Osa protein, which has been shown to interact with a SWI/SNF-like complex in flies. BAF250 possesses at least two conserved domains that could be important for its function. First, it has an AT-rich DNA interaction-type DNA-binding domain, which can specifically bind a DNA sequence known to be recognized by a SWI/SNF family-related complex at the β-globin locus. Second, BAF250 stimulates glucocorticoid receptor-dependent transcriptional activation, and the stimulation is sharply reduced when the C-terminal region of BAF250 is deleted. This region of BAF250 is capable of interacting directly with the glucocorticoid receptor in vitro. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.

Protein Interactions for Functional Genomics

2012 ◽  
Vol 3 (4) ◽  
pp. 15-30
Author(s):  
Pablo Minguez ◽  
Joaquin Dopazo
Keyword(s):  
Graph Theory ◽  
Protein Interactions ◽  
Biological Networks ◽  
State Of The Art ◽  
Protein Protein Interactions ◽  
Pairwise Interactions ◽  
Novel Approach ◽  
Functional Profiling ◽  
Available Resources

Here the authors review the state of the art in the use of protein-protein interactions (ppis) within the context of the interpretation of genomic experiments. They report the available resources and methodologies used to create a curated compilation of ppis introducing a novel approach to filter interactions. Special attention is paid in the complexity of the topology of the networks formed by proteins (nodes) and pairwise interactions (edges). These networks can be studied using graph theory and a brief introduction to the characterization of biological networks and definitions of the more used network parameters is also given. Also a report on the available resources to perform different modes of functional profiling using ppi data is provided along with a discussion on the approaches that have typically been applied into this context. They also introduce a novel methodology for the evaluation of networks and some examples of its application.

scholarly journals The 14-3-3 Proteins as Important Allosteric Regulators of Protein Kinases

2020 ◽  
Vol 21 (22) ◽  
pp. 8824
Author(s):  
Veronika Obsilova ◽  
Tomas Obsil
Keyword(s):  
Protein Interactions ◽  
Cell Cycle Progression ◽  
State Of The Art ◽  
Review Article ◽  
Protein Protein Interactions ◽  
Cycle Progression ◽  
Kinase Regulation ◽  
Functional Consequences ◽  
Allosteric Regulators ◽  
Structural Aspects

Phosphorylation by kinases governs many key cellular and extracellular processes, such as transcription, cell cycle progression, differentiation, secretion and apoptosis. Unsurprisingly, tight and precise kinase regulation is a prerequisite for normal cell functioning, whereas kinase dysregulation often leads to disease. Moreover, the functions of many kinases are regulated through protein–protein interactions, which in turn are mediated by phosphorylated motifs and often involve associations with the scaffolding and chaperon protein 14-3-3. Therefore, the aim of this review article is to provide an overview of the state of the art on 14-3-3-mediated kinase regulation, focusing on the most recent mechanistic insights into these important protein–protein interactions and discussing in detail both their structural aspects and functional consequences.

scholarly journals Correction: State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

2015 ◽  
Vol 44 (22) ◽  
pp. 8375-8375 ◽  
Author(s):  
Chunquan Sheng ◽  
Guoqiang Dong ◽  
Zhenyuan Miao ◽  
Wannian Zhang ◽  
Wei Wang
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
State Of The Art ◽  
Protein Protein Interactions

Correction for ‘State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors’ by Chunquan Sheng et al., Chem. Soc. Rev., 2015, DOI: 10.1039/c5cs00252d.

scholarly journals Selective Affimers Recognize BCL-2 Family Proteins Through Non-Canonical Structural Motifs

2019 ◽  
Author(s):  
Jennifer A. Miles ◽  
Fruzsina Hobor ◽  
James Taylor ◽  
Christian Tiede ◽  
Philip R. Rowell ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Cell Biology ◽  
Competitive Inhibition ◽  
Antibody Binding ◽  
Proof Of Concept ◽  
Protein Protein Interactions ◽  
The Family ◽  
Selective Ligands ◽  
Binding Cleft ◽  
Characterisation Methods

AbstractThe BCL-2 family is a challenging set of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are desirable as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-xL, BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective and potent recognition of their target BCL-2 protein. For anti-apoptotic targets, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug bound like conformation. These results indicate Affimers can be used as alternative templates to inspire design of selective BCL-2 family modulators, and provide proof-of-concept for the elaboration of selective non-antibody binding reagents for use in cell-biology applications.

scholarly journals Mutation effect estimation on protein–protein interactions using deep contextualized representation learning

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Guangyu Zhou ◽  
Muhao Chen ◽  
Chelsea J T Ju ◽  
Zheng Wang ◽  
Jyun-Yu Jiang ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Pair ◽  
Expert Knowledge ◽  
State Of The Art ◽  
Point Mutations ◽  
Representation Learning ◽  
Structural Features ◽  
Sequence Information ◽  
Protein Protein Interactions ◽  
Subtle Change

Abstract The functional impact of protein mutations is reflected on the alteration of conformation and thermodynamics of protein–protein interactions (PPIs). Quantifying the changes of two interacting proteins upon mutations is commonly carried out by computational approaches. Hence, extensive research efforts have been put to the extraction of energetic or structural features on proteins, followed by statistical learning methods to estimate the effects of mutations on PPI properties. Nonetheless, such features require extensive human labors and expert knowledge to obtain, and have limited abilities to reflect point mutations. We present an end-to-end deep learning framework, MuPIPR (Mutation Effects in Protein–protein Interaction PRediction Using Contextualized Representations), to estimate the effects of mutations on PPIs. MuPIPR incorporates a contextualized representation mechanism of amino acids to propagate the effects of a point mutation to surrounding amino acid representations, therefore amplifying the subtle change in a long protein sequence. On top of that, MuPIPR leverages a Siamese residual recurrent convolutional neural encoder to encode a wild-type protein pair and its mutation pair. Multi-layer perceptron regressors are applied to the protein pair representations to predict the quantifiable changes of PPI properties upon mutations. Experimental evaluations show that, with only sequence information, MuPIPR outperforms various state-of-the-art systems on estimating the changes of binding affinity for SKEMPI v1, and offers comparable performance on SKEMPI v2. Meanwhile, MuPIPR also demonstrates state-of-the-art performance on estimating the changes of buried surface areas. The software implementation is available at https://github.com/guangyu-zhou/MuPIPR.

scholarly journals The Glucocorticoid Receptor Represses the Positive Autoregulation of the Trout Estrogen Receptor Gene by Preventing the Enhancer Effect of a C/EBPβ-Like Protein

Endocrinology ◽  
2002 ◽  
Vol 143 (8) ◽  
pp. 2961-2974 ◽  
Author(s):  
Christèle Lethimonier ◽  
Gilles Flouriot ◽  
Olivier Kah ◽  
Bernadette Ducouret
Keyword(s):  
Glucocorticoid Receptor ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Receptor Gene ◽  
Inhibitory Effect ◽  
Proximal Region ◽  
Orphan Receptor ◽  
Protein Protein Interactions ◽  
Negative Effects ◽  
Er Positive

Abstract Stress and cortisol are known to have negative effects on vitellogenesis in oviparous species. This provides a physiological context in which to explore in more detail the molecular mechanisms involved in transcriptional interferences between two steroids receptors, the estradiol receptor (ER) and the glucocorticoid receptor (GR). We have previously shown that the cortisol inhibitory effect on rainbow trout (rt) vitellogenesis is the result of a repression of the estradiol-induced ER-positive autoregulation by activated GR. In the present study, we demonstrate that the GR repression involves a proximal region of the rtER promoter that is unable to bind GR. This inhibition is counteracted in part by the orphan receptor COUP-TF1 that has been previously shown to cooperate with ERs on the same promoter. A detailed analysis allowed us to identify a C/EBPβ-like protein that is implicated in both the maximal stimulatory effect of estradiol and the GR repression. Indeed, GR, through its DNA-binding domain, suppresses the binding of C/EBPβ on the rtER promoter by protein-protein interactions and thereby prevents the enhancer effect of this transcription factor.

Modulating the Bcl-2 Family of Apoptosis Suppressors for Potential Therapeutic Benefit in Cancer

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 226-230 ◽  
Author(s):  
Gordon C. Shore ◽  
Jean Viallet
Keyword(s):  
Protein Interactions ◽  
Therapeutic Benefit ◽  
Protein Protein Interactions ◽  
Cancer Treatments ◽  
The Family ◽  
Challenges And Opportunities ◽  
Apoptosis Pathways ◽  
Current Therapies ◽  
Cellular Oncogenes ◽  
Potential Therapeutic Benefit

Abstract Members of the BCL-2 family of proteins regulate and execute many cell intrinsic apoptosis pathways, including those arising from dysregulated expression of cellular oncogenes. Since pro-survival members of the family are often strongly elevated in diverse cancers, with the potential to confer resistance to both endogenous cell death stimuli and many cancer treatments, there has been intense interest to develop strategies to therapeutically modulate their activity. Although encouraging genetic and pharmacological preclinical proof of concept has been obtained, the challenge for clinical development will be to devise strategies that address the fact that multiple pro-survival members are typically up-regulated in a given cancer and the family operates primarily through protein-protein interactions. Moreover, since several current therapies themselves are known to stimulate the levels of one or more family members, there will be additional challenges (and opportunities) in exploiting this target in the clinic. In this review, we describe the rationale for targeting the BCL-2 family of apoptosis suppressors in cancer and the progress that has been made in modulating the family by small molecule antagonists.

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