Cysteine-based regulation of redox-sensitive Ras small GTPases

Messina, Samantha; G, De Simone; Ascenzi, Paolo

doi:10.1016/j.redox.2019.101282

Cited by 37 publications

(29 citation statements)

References 111 publications

(174 reference statements)

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“…CD69 expression in T lymphocytes is induced primarily via RAS-dependent Protein kinase C activation [42,43]. RAS is a redoxsensitive protein [44], and there is evidence that OS changes amino acid residues in RAS that result in altered CD69 expression [45]. Similarly, protein kinase C is also sensitive to RB changes and OS conditions that can produce structural modifications interfering with the activity of this kinase [46].…”

Section: Activation Of Lymphocytesmentioning

confidence: 99%

Oxidative Stress Compromises Lymphocyte Function in Neonatal Dairy Calves

2021

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Dairy calves are unable to mount an effective immune response during their first weeks of life, which contributes to increased disease susceptibility during this period. Oxidative stress (OS) diminishes the immune cell capabilities of humans and adult cows, and dairy calves also experience OS during their first month of life. However, the impact that OS may have on neonatal calf immunity remains unexplored. Thus, we aimed to evaluate the impact of OS on newborn calf lymphocyte functions. For this, we conducted two experiments. First, we assessed the association of OS status throughout the first month of age and the circulating concentrations of the cytokines interferon-gamma (IFN-γ) and interleukin (IL) 4, as well as the expression of cytokine-encoding genes IFNG, IL2, IL4, and IL10 in peripheral mononuclear blood cells (PBMCs) of 12 calves. Subsequently, we isolated PBMCs from another 6 neonatal calves to investigate in vitro the effect of OS on immune responses in terms of activation of lymphocytes, cytokine expression, and antibody production following stimulation with phorbol 12-myristate 13-acetate or bovine herpesvirus-1. The results were compared statistically through mixed models. Calves exposed to high OS status in their first month of age showed higher concentrations of IL-4 and expression of IL4 and IL10 and lower concentrations of IFN-γ and expression of IFNG and IL2 than calves exposed to lower OS. In vitro, OS reduced lymphocyte activation, production of antibodies, and protein and gene expression of key cytokines. Collectively, our results demonstrate that OS can compromise some immune responses of newborn calves. Hence, further studies are needed to explore the mechanisms of how OS affects the different lymphocyte subsets and the potential of ameliorating OS in newborn calves as a strategy to augment the functional capacity of calf immune cells, as well as enhance calves’ resistance to infections.

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Section: Activation Of Lymphocytesmentioning

confidence: 99%

Oxidative Stress Compromises Lymphocyte Function in Neonatal Dairy Calves

2021

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“…Interestingly, the most redox-sensitive site of Ras proteins, Cys118, is also located on L8. The oxidation of Cys118 (nitrosylation by reactive nitrogen species) affects tumorigenesis via influencing the nucleotide exchange rate and intrinsic GTPase activity in an isoform-specific manner [55], illustrating again the very real connection between these distant loci. In another study, local network entropy of the state 1-state 2 transitions of GTP-bound H-Ras based on parallel cascade selection MD simulations was calculated and the transition states of the process described.…”

Section: Nucleotide Binding and Exchangementioning

confidence: 99%

Dynamically encoded reactivity of Ras enzymes: opening new frontiers for drug discovery

Pálfy

Menyhárd

Perczel

2020

Cancer Metastasis Rev

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Decoding molecular flexibility in order to understand and predict biological processes-applying the principles of dynamicstructure-activity relationships (DSAR)-becomes a necessity when attempting to design selective and specific inhibitors of a protein that has overlapping interaction surfaces with its upstream and downstream partners along its signaling cascade. Ras proteins are molecular switches that meet this definition perfectly. The close-lying P-loop and the highly flexible switch I and switch II regions are the site of nucleotide-, assisting-, and effector-protein binding. Oncogenic mutations that also appear in this region do not cause easily characterized overall structural changes, due partly to the inherent conformational heterogeneity and pliability of these segments. In this review, we present an overview of the results obtained using approaches targeting Ras dynamics, such as nuclear magnetic resonance (NMR) measurements and experiment-based modeling calculations (mostly molecular dynamics (MD) simulations). These methodologies were successfully used to decipher the mutant-and isoformspecific nature of certain transient states, far-lying allosteric sites, and the internal interaction networks, as well as the interconnectivity of the catalytic and membrane-binding regions. This opens new therapeutic potential: the discovered interaction hotspots present hitherto not targeted, selective sites for drug design efforts in diverse locations of the protein matrix.

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“…Quantitative profiling of ADP ribosylation of RhoA/B/C in HT22 cell lysates was achieved by incorporating SILAC‐labeled internal standard in LC–MS/MS analyses (Schroder et al, 2018). Besides, reactive oxygen species (ROS)‐ and reactive nitrogen species (RNS)‐mediated modifications of Cys118 in Ras proteins, for example, S ‐glutathionylation and S ‐nitrosylation, were recently profiled by LC–MS/MS analysis (Ntai et al, 2018; Messina, De Simone, & Ascenzi, 2019).…”

Section: Proteomic Studies Of Gtp‐binding Proteinsmentioning

confidence: 99%

Global and Targeted Profiling of Gtp‐binding Proteins in Biological Samples by Mass Spectrometry

Huang

Wang

2020

Mass Spectrometry Reviews

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GTP‐binding proteins are among the most important enzyme families that are involved in a plethora of biological processes. However, owing to the enormous diversity of the nucleotide‐binding protein family, comprehensive analyses of the expression level, structure, activity, and regulatory mechanisms of GTP‐binding proteins remain challenging with the use of conventional approaches. The many advances in mass spectrometry (MS) instrumentation and data acquisition methods, together with a variety of enrichment approaches in sample preparation, render MS a powerful tool for the comprehensive characterizations of the activities and expression levels of various GTP‐binding proteins. We review herein the recent developments in the application of MS‐based techniques, together with general and widely used affinity enrichment approaches, for the proteome‐wide and targeted capture, identification, and quantification of GTP‐binding proteins. The working principles, advantages, and limitations of various strategies for profiling the expression level, activity, posttranslational modifications, and interactome of GTP‐binding proteins are discussed. It can be envisaged that future applications of MS‐based proteomics will lead to a better understanding about the roles of GTP‐binding proteins in different biological processes and human diseases. © 2020 John Wiley & Sons Ltd. Mass Spec Rev.

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Cysteine-based regulation of redox-sensitive Ras small GTPases

Cited by 37 publications

References 111 publications

Oxidative Stress Compromises Lymphocyte Function in Neonatal Dairy Calves

Oxidative Stress Compromises Lymphocyte Function in Neonatal Dairy Calves

Dynamically encoded reactivity of Ras enzymes: opening new frontiers for drug discovery

Global and Targeted Profiling of Gtp‐binding Proteins in Biological Samples by Mass Spectrometry

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