scholarly journals Role of glutathiolation in preservation, restoration and regulation of protein function

IUBMB Life ◽  
2007 ◽  
Vol 59 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Bradford Hill ◽  
Aruni Bhatnagar
Keyword(s):  
Protein Function

scholarly journals PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dawei Chen ◽  
Zhenguo Zhao ◽  
Lu Chen ◽  
Qinghua Li ◽  
Jixue Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Protein Function ◽  
Vital Role ◽  
Normal Tissues ◽  
Mechanistic Analysis ◽  
Highly Correlated ◽  
Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

scholarly journals Genotyping of 2 Cholesteryl Ester Transfer Protein Gene Variants Among Coronary Artery Disease Patients

2020 ◽  
Vol 5 (3) ◽  
pp. 96-100
Author(s):  
Saeid Morovvati ◽  
Nima Kazemi Koohbanani ◽  
Iman Salahshouri Far ◽  
Fatemeh Karami
Keyword(s):  
Coronary Artery ◽  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Protein Function ◽  
Cholesterol Metabolism ◽  
Density Lipoprotein ◽  
Transfer Protein ◽  
Polymerase Chain ◽  
Artery Disease

Introduction: Coronary artery diseases (CAD) are still among the top causes of death in most populations. The polymorphisms of the cholesteryl ester transfer protein (CETP) gene can influence the risk of CAD through modulating cholesterol metabolism. In this regard, the current study aimed to determine the role of the 2 important CETP gene polymorphisms in CAD patients. Methods: To this end, DNA was extracted from the whole blood of 100 CAD patients and 100 healthy controls and then subjected to polymerase chain reaction-restriction fragment length polymorphism for the genotyping of rs5882 and rs708272 polymorphisms.Results: Based on the results, no meaningful association was found between rs5882 and rs708272 polymorphisms, neither separately nor in combination, and the risk of CAD. However, the risk of CAD significantly increased in male rs5882 polymorphism carriers (P = 0.01). Finally, no significant association was demonstrated between serum high-density lipoprotein levels and the genotypes or alleles of neither rs5882 nor rs708272 polymorphism. Conclusion: Despite the finding regarding the lack of an association between CAD and the studied polymorphisms of the CETP gene, the importance of those variants in CETP protein function and CAD pathogenesis warrants further investigation on larger populations.

scholarly journals Activity of the Pore-Forming Virulence Factor Listeriolysin O Is Reversibly Inhibited by Naturally Occurring S-Glutathionylation

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Jonathan L. Portman ◽  
Qiongying Huang ◽  
Michelle L. Reniere ◽  
Anthony T. Iavarone ◽  
Daniel A. Portnoy
Keyword(s):  
Protein Function ◽  
Inhibitory Effect ◽  
Cysteine Residue ◽  
Infection Model ◽  
Listeriolysin O ◽  
Content Type ◽  
Pore Forming Proteins

ABSTRACT Cholesterol-dependent cytolysins (CDCs) represent a family of homologous pore-forming proteins secreted by many Gram-positive bacterial pathogens. CDCs mediate membrane binding partly through a conserved C-terminal undecapeptide, which contains a single cysteine residue. While mutational changes to other residues in the undecapeptide typically have severe effects, mutation of the cysteine residue to alanine has minor effects on overall protein function. Thus, the role of this highly conserved reactive cysteine residue remains largely unknown. We report here that the CDC listeriolysin O (LLO), secreted by the facultative intracellular pathogen Listeria monocytogenes, was posttranslationally modified by S-glutathionylation at this conserved cysteine residue and that either endogenously synthesized or exogenously added glutathione was sufficient to form this modification. When recapitulated with purified protein in vitro, this modification completely ablated the activity of LLO, and this inhibitory effect was fully reversible by treatment with reducing agents. A cysteine-to-alanine mutation in LLO rendered the protein completely resistant to inactivation by S-glutathionylation, and a mutant expressing this mutation retained full hemolytic activity. A mutant strain of L. monocytogenes expressing the cysteine-to-alanine variant of LLO was able to infect and replicate within bone marrow-derived macrophages indistinguishably from the wild type in vitro, yet it was attenuated 4- to 6-fold in a competitive murine infection model in vivo. This study suggests that S-glutathionylation may represent a mechanism by which CDC-family proteins are posttranslationally modified and regulated and help explain an evolutionary pressure to retain the highly conserved undecapeptide cysteine.

Insights into biological functions across species: examining the role of Rab proteins in YIP1 family function

2005 ◽  
Vol 33 (4) ◽  
pp. 614-618 ◽  
Author(s):  
C.Z. Chen ◽  
R.N. Collins
Keyword(s):  
Membrane Proteins ◽  
Protein Function ◽  
Evolutionary Conservation ◽  
Biological Role ◽  
Rab Proteins ◽  
Biological Functions ◽  
Human Homologue ◽  
Family Function ◽  
Evolutionarily Conserved

The YIP1 family comprises an evolutionarily conserved group of membrane proteins, which share the ability to bind di-prenylated Rab proteins. The biochemical capability of YIP1 family proteins suggests a possible role in the cycle of physical localization of Rab proteins between their cognate membranes and the cytosol. YIP1 is essential for viability in yeast and a deletion of YIP1 can be rescued with the human homologue YIP1A. We have made use of this evolutionary conservation of function to generate a series of mutant alleles of YIP1 to investigate the biological role of Yip1p. Our findings indicate evidence for the participation of Yip1p in both Rab and COPII protein function; at present, we are not able to distinguish between the models that these roles represent, i.e. independent or dependent activities of Yip1p.

scholarly journals Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

2020 ◽  
Vol 21 (24) ◽  
pp. 9451
Author(s):  
Marijn N. Maas ◽  
Jordi C. J. Hintzen ◽  
Miriam R. B. Porzberg ◽  
Jasmin Mecinović
Keyword(s):  
Protein Function ◽  
Genetic Disorders ◽  
Enzymatic Reactions ◽  
Lysine Methylation ◽  
Nucleosome Assembly ◽  
Cellular Processes ◽  
Subsequent Effect ◽  
Control Protein ◽  
Epigenetic Processes

Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly.

scholarly journals Role of the cysteine residues in Arabidopsis thaliana cyclophilin CYP20-3 in peptidyl-prolyl cis–trans isomerase and redox-related functions

2006 ◽  
Vol 401 (1) ◽  
pp. 287-297 ◽  
Author(s):  
Miriam Laxa ◽  
Janine König ◽  
Karl-Josef Dietz ◽  
Andrea Kandlbinder
Keyword(s):  
Conformational Changes ◽  
Protein Function ◽  
Redox Regulation ◽  
Catalytic Efficiency ◽  
Structural Rearrangement ◽  
Disulfide Bridge ◽  
Cysteine Residues ◽  
Active Centre ◽  
Independent Functions

Cyps (cyclophilins) are ubiquitous proteins of the immunophilin superfamily with proposed functions in protein folding, protein degradation, stress response and signal transduction. Conserved cysteine residues further suggest a role in redox regulation. In order to get insight into the conformational change mechanism and functional properties of the chloroplast-located CYP20-3, site-directed mutagenized cysteine→serine variants were generated and analysed for enzymatic and conformational properties under reducing and oxidizing conditions. Compared with the wild-type form, elimination of three out of the four cysteine residues decreased the catalytic efficiency of PPI (peptidyl-prolyl cis–trans isomerase) activity of the reduced CYP20-3, indicating a regulatory role of dithiol–disulfide transitions in protein function. Oxidation was accompanied by conformational changes with a predominant role in the structural rearrangement of the disulfide bridge formed between Cys54 and Cys171. The rather negative Em (midpoint redox potential) of −319 mV places CYP20-3 into the redox hierarchy of the chloroplast, suggesting the activation of CYP20-3 in the light under conditions of limited acceptor availability for photosynthesis as realized under environmental stress. Chloroplast Prx (peroxiredoxins) were identified as interacting partners of CYP20-3 in a DNA-protection assay. A catalytic role in the reduction of 2-Cys PrxA and 2-Cys PrxB was assigned to Cys129 and Cys171. In addition, it was shown that the isomerization and disulfide-reduction activities are two independent functions of CYP20-3 that both are regulated by the redox state of its active centre.

Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype

2018 ◽  
Vol 55 (11) ◽  
pp. 779-784 ◽  
Author(s):  
Alina Kurolap ◽  
Orly Eshach-Adiv ◽  
Claudia Gonzaga-Jauregui ◽  
Katya Dolnikov ◽  
Adi Mory ◽  
...  
Keyword(s):  
Barrier Function ◽  
Protein Function ◽  
Transmembrane Domain ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Protein Loss ◽  
Protein Losing Enteropathy ◽  
Family Based ◽  
And Function

BackgroundIntestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency.ObjectiveTo genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years.MethodsFamily-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silico analyses were used to predict variant impact on protein structure and function.ResultsWe identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein’s transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected.ConclusionsBiallelic missense variants in PLVAP can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP’s importance in EC barrier function in the gut.

scholarly journals The role of whey acidic protein four-disulfide-core proteins in respiratory health and disease

2017 ◽  
Vol 398 (4) ◽  
pp. 425-440 ◽  
Author(s):  
Donna M. Small ◽  
Declan F. Doherty ◽  
Caoifa M. Dougan ◽  
Sinéad Weldon ◽  
Clifford C. Taggart
Keyword(s):  
Protein Function ◽  
Respiratory Health ◽  
Whey Acidic Protein ◽  
Acidic Protein ◽  
Current Evidence ◽  
Core Proteins ◽  
Health And Disease ◽  
Low Molecular Weight Proteins ◽  
Potential Therapeutics

Abstract Members of the whey acidic protein (WAP) or WAP four-disulfide-core (WFDC) family of proteins are a relatively under-explored family of low molecular weight proteins. The two most prominent WFDC proteins, secretory leukocyte protease inhibitor (SLPI) and elafin (or the precursor, trappin-2), have been shown to possess multiple functions including anti-protease, anti-bacterial, anti-viral and anti-inflammatory properties. It is therefore of no surprise that both SLPI and elafin/trappin-2 have been developed as potential therapeutics. Given the abundance of SLPI and elafin/trappin-2 in the human lung, most work in the area of WFDC research has focused on the role of WFDC proteins in protecting the lung from proteolytic attack. In this review, we will outline the current evidence regarding the expanding role of WFDC protein function with a focus on WFDC activity in lung disease as well as emerging data regarding the function of some of the more recently described WFDC proteins.

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