scholarly journals Structural and Functional Consequences Induced by Post-Translational Modifications in α-Defensins

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Enrico Balducci ◽  
Alessio Bonucci ◽  
Monica Picchianti ◽  
Rebecca Pogni ◽  
Eleonora Talluri
Keyword(s):  
Antimicrobial Peptide ◽  
Marked Change ◽  
Antibacterial Activities ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Adp Ribosylation ◽  
Functional Consequences ◽  
Adp Ribosyltransferase ◽  
Guanidino Group ◽  
Ribose Moiety

HNP-1 is an antimicrobial peptide that undergoes proteolytic cleavage to become a mature peptide. This process represents the mechanism commonly used by the cells to obtain a fully active antimicrobial peptide. In addition, it has been recently described that HNP-1 is recognized as substrate by the arginine-specific ADP-ribosyltransferase-1. Arginine-specific mono-ADP-ribosylation is an enzyme-catalyzed post-translational modification in which NAD+ serves as donor of the ADP-ribose moiety, which is transferred to the guanidino group of arginines in target proteins. While the arginine carries one positive charge, the ADP-ribose is negatively charged at the phosphate moieties at physiological pH. Therefore, the attachment of one or more ADP-ribose units results in a marked change of cationicity. ADP-ribosylation of HNP-1 drastically reduces its cytotoxic and antibacterial activities. While the chemotactic activity of HNP-1 remains unaltered, its ability to induce interleukin-8 production is enhanced. The arginine 14 of HNP-1 modified by the ADP-ribose is in some cases processed into ornithine, perhaps representing a different modality in the regulation of HNP-1 activities.

scholarly journals ADP-ribosylation of integrin α7 modulates the binding of integrin α7β1 to laminin

2004 ◽  
Vol 385 (1) ◽  
pp. 309-317 ◽  
Author(s):  
Zhefeng ZHAO ◽  
Joanna GRUSZCZYNSKA-BIEGALA ◽  
Anna ZOLKIEWSKA
Keyword(s):  
C2c12 Myotubes ◽  
Post Translational Modification ◽  
Integrin Β1 ◽  
Adp Ribosylation ◽  
In Vitro Binding ◽  
Vitro Binding ◽  
C2c12 Skeletal Muscle Cells ◽  
Adp Ribosyltransferase

The extracellular domain of integrin α7 is ADP-ribosylated by an arginine-specific ecto-ADP-ribosyltransferase after adding exogenous NAD+ to intact C2C12 skeletal muscle cells. The effect of ADP-ribosylation on the structure or function of integrin α7β1 has not been explored. In the present study, we show that ADP-ribosylation of integrin α7 takes place exclusively in differentiated myotubes and that this post-translational modification modulates the affinity of α7β1 dimer for its ligand, laminin. ADP-ribosylation in the 37-kDa ‘stalk’ region of α7 that takes place at micromolar NAD+ concentrations increases the binding of the α7β1 dimer to laminin. Increased in vitro binding of integrin α7β1 to laminin after ADP-ribosylation of the 37-kDa fragment of α7 requires the presence of Mn2+ and it is not observed in the presence of Mg2+. In contrast, ADP-ribosylation of the 63-kDa N-terminal region comprising the ligand-binding site of α7 that occurs at approx. 100 μM NAD+ inhibits the binding of integrin α7β1 to laminin. Furthermore, incubation of C2C12 myotubes with NAD+ increases the expression of an epitope on integrin β1 subunit recognized by monoclonal antibody 9EG7. We discuss our results based on the current models of integrin activation. We also hypothesize that ADP-ribosylation may represent a mechanism of regulation of integrin α7β1 function in myofibres in vivo when the continuity of the membrane is compromised and NAD+ is available as a substrate for ecto-ADP-ribosylation.

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.

ADP-ribosylation and intracellular traffic: an emerging role for PARP enzymes

2019 ◽  
Vol 47 (1) ◽  
pp. 357-370 ◽  
Author(s):  
Giovanna Grimaldi ◽  
Daniela Corda
Keyword(s):  
Intracellular Transport ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Intracellular Traffic ◽  
Adp Ribosylation ◽  
Cell Responses ◽  
Physiological Processes ◽  
Dependent Cell ◽  
Ribose Moiety

AbstractADP-ribosylation is an ancient and reversible post-translational modification (PTM) of proteins, in which the ADP-ribose moiety is transferred from NAD+ to target proteins by members of poly-ADP-ribosyl polymerase (PARP) family. The 17 members of this family have been involved in a variety of cellular functions, where their regulatory roles are exerted through the modification of specific substrates, whose identification is crucial to fully define the contribution of this PTM. Evidence of the role of the PARPs is now available both in the context of physiological processes and of cell responses to stress or starvation. An emerging role of the PARPs is their control of intracellular transport, as it is the case for tankyrases/PARP5 and PARP12. Here, we discuss the evidence pointing at this novel aspect of PARPs-dependent cell regulation.

scholarly journals Poly(ADP-ribosylation) protects maternally derived histones from proteolysis after fertilization

1999 ◽  
Vol 343 (1) ◽  
pp. 95-98 ◽  
Author(s):  
Violeta MORIN ◽  
Freddy DIAZ ◽  
Martin MONTECINO ◽  
Linda FOTHERGILL-GILMORE ◽  
Marcia PUCHI ◽  
...  
Keyword(s):  
Sea Urchins ◽  
Cysteine Proteinase ◽  
Histone Variants ◽  
Nuclear Proteins ◽  
Post Translational Modification ◽  
Cleavage Stage ◽  
Adp Ribosylation ◽  
Ribose Moiety

Fertilization in sea urchins is followed by the replacement of sperm-specific histones by cleavage-stage histone variants recruited from maternal stores. Such remodelling of zygote chromatin involves a cysteine proteinase that degrades the sperm-specific histones in a selective manner, leaving the maternal cleavage-stage histone variants intact. The mechanism that determines the selectivity of the sperm-histone-selective proteinase (SpH-proteinase) was analysed by focusing on the post-translational modification status of both sets of histones. It has previously been reported that only native cleavage-stage histones are poly(ADP-ribosylated), whereas the sperm-specific histones are not modified. To determine whether the poly(ADP-ribose) moiety afforded protection from degradation, the ADP-ribose polymers were removed from the cleavage-stage histones in vitro; these proteins were then assayed as potential substrates of the SpH-proteinase. Strikingly, the cleavage-stage histone variants were extensively degraded after the enzymic removal of their ADP-ribose moieties. In addition, the SpH cysteine proteinase was not inhibited by isolated poly(ADP-ribose) polymers. Consequently, only poly(ADP-ribosylated) cleavage-stage histone variants are protected from proteolysis. These results demonstrate a novel role for this type of post-translational modification, namely the protection of nuclear proteins against nuclear proteinases after fertilization.

scholarly journals A novel predicted ADP-ribosyltransferase-like family conserved in eukaryotic evolution

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11051
Author(s):  
Zbigniew Wyżewski ◽  
Marcin Gradowski ◽  
Marianna Krysińska ◽  
Małgorzata Dudkiewicz ◽  
Krzysztof Pawłowski
Keyword(s):  
Active Site ◽  
Pathogen Detection ◽  
Defense Mechanism ◽  
Innate Immune ◽  
Covalent Attachment ◽  
The Novel ◽  
Post Translational Modification ◽  
Eukaryotic Evolution ◽  
Adp Ribosylation ◽  
Adp Ribosyltransferase

The presence of many completely uncharacterized proteins, even in well-studied organisms such as humans, seriously hampers full understanding of the functioning of the living cells. ADP-ribosylation is a common post-translational modification of proteins; also nucleic acids and small molecules can be modified by the covalent attachment of ADP-ribose. This modification, important in cellular signalling and infection processes, is usually executed by enzymes from the large superfamily of ADP-ribosyltransferases (ARTs). Here, using bioinformatics approaches, we identify a novel putative ADP-ribosyltransferase family, conserved in eukaryotic evolution, with a divergent active site. The hallmark of these proteins is the ART domain nestled between flanking leucine-rich repeat (LRR) domains. LRRs are typically involved in innate immune surveillance. The novel family appears as putative novel ADP-ribosylation-related actors, most likely pseudoenzymes. Sequence divergence and lack of clearly detectable “classical” ART active site suggests the novel domains are pseudoARTs, yet atypical ART activity, or alternative enzymatic activity cannot be excluded. We propose that this family, including its human member LRRC9, may be involved in an ancient defense mechanism, with analogies to the innate immune system, and coupling pathogen detection to ADP-ribosyltransfer or other signalling mechanisms.

scholarly journals ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

2021 ◽  
Vol 22 (19) ◽  
pp. 10829
Author(s):  
Palmiro Poltronieri ◽  
Masanao Miwa ◽  
Mitsuko Masutani
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Responses ◽  
Cancer Control ◽  
Large Set ◽  
Post Translational Modification ◽  
Covalent Bonds ◽  
Post Translational Modifications ◽  
Adp Ribosylation ◽  
Oncological Diseases ◽  
Rapid Pace

Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

scholarly journals A novel predicted ADP-ribosyltransferase family conserved in eukaryotic evolution

2020 ◽  
Author(s):  
Zbigniew Wyżewski ◽  
Marcin Gradowski ◽  
Marianna Krysińska ◽  
Małgorzata Dudkiewicz ◽  
Krzysztof Pawłowski
Keyword(s):  
Pathogen Detection ◽  
Defense Mechanism ◽  
Immune Surveillance ◽  
Innate Immune ◽  
Covalent Attachment ◽  
Post Translational Modification ◽  
Eukaryotic Evolution ◽  
Adp Ribosylation ◽  
Infection Processes ◽  
Adp Ribosyltransferase

AbstractThe presence of many completely uncharacterized proteins, even in well-studied organisms such as humans, seriously hampers full understanding of the functioning of the living cells. ADP-ribosylation is a common post-translational modification of proteins; also nucleic acids and small molecules can be modified by the covalent attachment of ADP-ribose. This modification, important in cellular signalling and infection processes, is usually executed by enzymes from the large superfamily of ADP-ribosyltransferases (ARTs)Here, using bioinformatics approaches, we identify a novel putative ADP-ribosyltransferase family, conserved in eukaryotic evolution, with a divergent active site. The hallmark of these proteins is the ART domain nestled between flanking leucine-rich repeat (LRR) domains. LRRs are involved in innate immune surveillance.The novel family appears as likely novel ADP-ribosylation “writers”, previously unnoticed new players in cell signaling by this emerging post-translational modification. We propose that this family, including its human member LRRC9, may be involved in an ancient defense mechanism, with analogies to the innate immune system, and coupling pathogen detection to ADP-ribosyltransfer signalling.

scholarly journals Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

2021 ◽  
Author(s):  
Palmiro Poltronieri ◽  
Masanao Miwa ◽  
Mitsuko Masutani
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Responses ◽  
Cancer Control ◽  
Large Set ◽  
Post Translational Modification ◽  
Covalent Bonds ◽  
Post Translational Modifications ◽  
Adp Ribosylation ◽  
Oncological Diseases ◽  
Rapid Pace

Among post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, assigning to this PTM a large set of functions, including DNA repair, transcription and cell signaling. This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing MAR/PAR cycling in cancers. Of note, there is potential for application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

RNF114 suppresses tumour metastasis through the regulation of PARP10

2020 ◽  
Author(s):  
Yahui Zhao ◽  
Xiao Liang ◽  
Li Wei ◽  
Yao Liu ◽  
Juan Liu ◽  
...  
Keyword(s):  
Migration And Invasion ◽  
Aurora A Kinase ◽  
Post Translational Modification ◽  
Western Blots ◽  
Adp Ribosylation ◽  
Tumour Metastasis ◽  
Adp Ribosyltransferase ◽  
Downstream Signalling Pathway

Abstract Background ADP-ribosylation is a multifunctional post-translational modification catalysed by intracellular ADP-ribosyltransferases. Previously, we demonstrated that the mono-ADP-ribosyltransferase PARP10 suppresses tumour metastasis through the negative regulation of Aurora A kinase activity. However, the mechanisms of PARP10 regulation and modification were unclear. Methods Interaction of RNF114 and PARP10 was identified by exogenous and endogenous reciprocal immunoprecipitation (IP) assays and pull-down assays. Ubiquitination of PARP10 by RNF114 was analysed by in vivo ubiquitination assays. Potential effects of ubiquitination on PARP10’s activity was detected by western blots and pull-down assays. Potential role of RNF114 in tumour metastasis were determined by migration and invasion assays and in vivo metastasis assay. Results That E3 ubiquitin ligase RNF114 is a partner of PARP10 was identified by IP assays. The auto-mono-ADP-ribosylation of PARP10 is required for the interaction of RNF114 and PARP10. RNF114 ubiquitinates PARP10 through K27-linked polyubiquitination, which enhances PARP10 enzymatic activity. Moreover, RNF114 deficiency promotes tumour cell migration and tumour metastasis through the regulation of PARP10 and its downstream signalling pathway. Conclusions Our findings identify RNF114 as a novel functional regulator of PARP10 and provide evidence of crosstalk between the components of K27-linked polyubiquitination and mono-ADP ribosylation.

Dicarbonyl derived post-translational modifications: chemistry bridging biology and aging-related disease

2020 ◽  
Vol 64 (1) ◽  
pp. 97-110
Author(s):  
Christian Sibbersen ◽  
Mogens Johannsen
Keyword(s):  
Mass Spectrometry ◽  
Future Research ◽  
Amino Acid Residues ◽  
Post Translational Modification ◽  
Dicarbonyl Compounds ◽  
Protein Targets ◽  
Post Translational Modifications ◽  
Reactive Protein ◽  
Glycation End Products ◽  
Direct Mass Spectrometry

Abstract In living systems, nucleophilic amino acid residues are prone to non-enzymatic post-translational modification by electrophiles. α-Dicarbonyl compounds are a special type of electrophiles that can react irreversibly with lysine, arginine, and cysteine residues via complex mechanisms to form post-translational modifications known as advanced glycation end-products (AGEs). Glyoxal, methylglyoxal, and 3-deoxyglucosone are the major endogenous dicarbonyls, with methylglyoxal being the most well-studied. There are several routes that lead to the formation of dicarbonyl compounds, most originating from glucose and glucose metabolism, such as the non-enzymatic decomposition of glycolytic intermediates and fructosyl amines. Although dicarbonyls are removed continuously mainly via the glyoxalase system, several conditions lead to an increase in dicarbonyl concentration and thereby AGE formation. AGEs have been implicated in diabetes and aging-related diseases, and for this reason the elucidation of their structure as well as protein targets is of great interest. Though the dicarbonyls and reactive protein side chains are of relatively simple nature, the structures of the adducts as well as their mechanism of formation are not that trivial. Furthermore, detection of sites of modification can be demanding and current best practices rely on either direct mass spectrometry or various methods of enrichment based on antibodies or click chemistry followed by mass spectrometry. Future research into the structure of these adducts and protein targets of dicarbonyl compounds may improve the understanding of how the mechanisms of diabetes and aging-related physiological damage occur.

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