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Sigrun Lange - One of the best experts on this subject based on the ideXlab platform.
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Extracellular Vesicles and Post-Translational Protein Deimination Signatures in Mollusca-The Blue Mussel (Mytilus edulis), Soft Shell Clam (Mya arenaria), Eastern Oyster (Crassostrea virginica) and Atlantic Jacknife Clam (Ensis leei).
Biology, 2020Co-Authors: Timothy J. Bowden, Igor Kraev, Sigrun LangeAbstract:Oysters and clams are important for food security and of commercial value worldwide. They are affected by anthropogenic changes and opportunistic pathogens and can be indicators of changes in ocean environments. Therefore, studies into biomarker discovery are of considerable value. This study aimed at assessing extracellular vesicle (EV) signatures and post-translational Protein deimination profiles of hemolymph from four commercially valuable Mollusca species, the blue mussel (Mytilus edulis), soft shell clam (Mya arenaria), Eastern oyster (Crassostrea virginica), and Atlantic jacknife clam (Ensis leei). EVs form part of cellular communication by transporting Protein and genetic cargo and play roles in immunity and host–pathogen interactions. Protein deimination is a post-translational modification caused by peptidylarginine deiminases (PADs), and can facilitate Protein Moonlighting in health and disease. The current study identified hemolymph-EV profiles in the four Mollusca species, revealing some species differences. Deiminated Protein candidates differed in hemolymph between the species, with some common targets between all four species (e.g., histone H3 and H4, actin, and GAPDH), while other hits were species-specific; in blue mussel these included heavy metal binding Protein, heat shock Proteins 60 and 90, 2-phospho-D-glycerate hydrolyase, GTP cyclohydrolase feedback regulatory Protein, sodium/potassium-transporting ATPase, and fibrinogen domain containing Protein. In soft shell clam specific deimination hits included dynein, MCM3-associated Protein, and SCRN. In Eastern oyster specific deimination hits included muscle LIM Protein, beta-1,3-glucan-binding Protein, myosin heavy chain, thaumatin-like Protein, vWFA domain-containing Protein, BTB domain-containing Protein, amylase, and beta-catenin. Deiminated Proteins specific to Atlantic jackknife clam included nacre c1q domain-containing Protein and PDZ domain-containing Protein In addition, some Proteins were common as deiminated targets between two or three of the Bivalvia species under study (e.g., EP Protein, C1q domain containing Protein, histone H2B, tubulin, elongation factor 1-alpha, dominin, extracellular superoxide dismutase). Protein interaction network analysis for the deiminated Protein hits revealed major pathways relevant for immunity and metabolism, providing novel insights into post-translational regulation via deimination. The study contributes to EV characterization in diverse taxa and understanding of roles for PAD-mediated regulation of immune and metabolic pathways throughout phylogeny.
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Putative Roles for Peptidylarginine Deiminases in COVID-19.
International journal of molecular sciences, 2020Co-Authors: Elif Damla Arısan, Pinar Uysal-onganer, Sigrun LangeAbstract:Peptidylarginine deiminases (PADs) are a family of calcium-regulated enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to Protein Moonlighting in health and disease. PADs are implicated in a range of inflammatory and autoimmune conditions, in the regulation of extracellular vesicle (EV) release, and their roles in infection and immunomodulation are known to some extent, including in viral infections. In the current study we describe putative roles for PADs in COVID-19, based on in silico analysis of BioProject transcriptome data (PRJNA615032 BioProject), including lung biopsies from healthy volunteers and SARS-CoV-2-infected patients, as well as SARS-CoV-2-infected, and mock human bronchial epithelial NHBE and adenocarcinoma alveolar basal epithelial A549 cell lines. In addition, BioProject Data PRJNA631753, analysing patients tissue biopsy data (n = 5), was utilised. We report a high individual variation observed for all PADI isozymes in the patients’ tissue biopsies, including lung, in response to SARS-CoV-2 infection, while PADI2 and PADI4 mRNA showed most variability in lung tissue specifically. The other tissues assessed were heart, kidney, marrow, bowel, jejunum, skin and fat, which all varied with respect to mRNA levels for the different PADI isozymes. In vitro lung epithelial and adenocarcinoma alveolar cell models revealed that PADI1, PADI2 and PADI4 mRNA levels were elevated, but PADI3 and PADI6 mRNA levels were reduced in SARS-CoV-2-infected NHBE cells. In A549 cells, PADI2 mRNA was elevated, PADI3 and PADI6 mRNA was downregulated, and no effect was observed on the PADI4 or PADI6 mRNA levels in infected cells, compared with control mock cells. Our findings indicate a link between PADI expression changes, including modulation of PADI2 and PADI4, particularly in lung tissue, in response to SARS-CoV-2 infection. PADI isozyme 1–6 expression in other organ biopsies also reveals putative links to COVID-19 symptoms, including vascular, cardiac and cutaneous responses, kidney injury and stroke. KEGG and GO pathway analysis furthermore identified links between PADs and inflammatory pathways, in particular between PAD4 and viral infections, as well as identifying links for PADs with a range of comorbidities. The analysis presented here highlights roles for PADs in-host responses to SARS-CoV-2, and their potential as therapeutic targets in COVID-19.
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deiminated Proteins in extracellular vesicles and serum of llama lama glama novel insights into camelid immunity
Molecular Immunology, 2020Co-Authors: Michael F Criscitiello, Igor Kraev, Sigrun LangeAbstract:Peptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which post-translationally convert arginine into citrulline in target Proteins in an irreversible manner, causing functional and structural changes in target Proteins. Protein deimination causes generation of neo-epitopes, affects gene regulation and also allows for Protein Moonlighting. Furthermore, PADs have been found to be a phylogenetically conserved regulator for extracellular vesicle (EVs) release. EVs are found in most body fluids and participate in cellular communication via transfer of cargo Proteins and genetic material. In this study, post-translationally deiminated Proteins in serum and serum-EVs are described for the first time in camelids, using the llama (Lama glama L. 1758) as a model animal. We report a poly-dispersed population of llama serum EVs, positive for phylogenetically conserved EV-specific markers and characterised by TEM. In serum, 103 deiminated Proteins were overall identified, including key immune and metabolic mediators including complement components, immunoglobulin-based nanobodies, adiponectin and heat shock Proteins. In serum, 60 deiminated Proteins were identified that were not in EVs, and 25 deiminated Proteins were found to be unique to EVs, with 43 shared deiminated Protein hits between both serum and EVs. Deiminated histone H3, a marker of neutrophil extracellular trap formation, was also detected in llama serum. PAD homologues were identified in llama serum by Western blotting, via cross reaction with human PAD antibodies, and detected at an expected 70 kDa size. This is the first report of deiminated Proteins in serum and EVs of a camelid species, highlighting a hitherto unrecognized post-translational modification in key immune and metabolic Proteins in camelids, which may be translatable to and inform a range of human metabolic and inflammatory pathologies.
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Complement component C4-like Protein in Atlantic cod (Gadus morhua L.) - Detection in ontogeny and identification of post-translational deimination in serum and extracellular vesicles.
Developmental and comparative immunology, 2019Co-Authors: Sigrun Lange, Bergljót Magnadóttir, Igor Kraev, Alister W. DoddsAbstract:The complement system is a critical part of teleost immune defences, with complement component C4 forming part of the classical and lectin pathways. Cod C4-like Protein was isolated from plasma, specific antibodies generated and C4-like Protein was assessed in cod sera, mucus and in extracellular vesicles (EVs) from serum and mucus. Higher levels of C4-like Protein were detected in serum- than mucus-derived EVs. Post-translational deimination, caused by conversion of arginine into citrulline, can affect Protein structure and function. Here we detected deiminated forms of C4-like Protein in cod serum and at lower levels in mucus. C4-like Protein was also found in deiminated form at low levels in EVs from both serum and mucus. C4-like Protein was assessed by immunohistochemistry in cod larvae and detected in a range of organs including in liver, kidney, gut, muscle, skin and mucus, as well as in neuronal tissues of the brain, spinal cord and eye. This abundance of C4-like Protein during early development may indicate roles in tissue remodelling, in addition to immune defences. The presence of deiminated C4-like Protein in serum and mucosa, as well as in EVs, may suggest C4 Protein Moonlighting via post-translational deimination.
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Post-translational Protein deimination in cod (Gadus morhua L.) ontogeny novel roles in tissue remodelling and mucosal immune defences?
Developmental and comparative immunology, 2018Co-Authors: Bergljót Magnadóttir, Polly M. Hayes, Mariya Hristova, Birkir Thor Bragason, Anthony P. Nicholas, Alister W. Dodds, Sigríður Guðmundsdóttir, Sigrun LangeAbstract:Abstract Peptidylarginine deiminases (PADs) are calcium dependent enzymes with physiological and pathophysiological roles conserved throughout phylogeny. PADs promote post-translational deimination of Protein arginine to citrulline, altering the structure and function of target Proteins. Deiminated Proteins were detected in the early developmental stages of cod from 11 days post fertilisation to 70 days post hatching. Deiminated Proteins were present in mucosal surfaces and in liver, pancreas, spleen, gut, muscle, brain and eye during early cod larval development. Deiminated Protein targets identified in skin mucosa included nuclear histones; cytoskeletal Proteins such as tubulin and beta-actin; metabolic and immune related Proteins such as galectin, mannan-binding lectin, toll-like receptor, kininogen, Beta2-microglobulin, aldehyde dehydrogenase, bloodthirsty and preproapolipoProtein A-I. Deiminated histone H3, a marker for anti-pathogenic neutrophil extracellular traps, was particularly elevated in mucosal tissues in immunostimulated cod larvae. PAD-mediated Protein deimination may facilitate Protein Moonlighting, allowing the same Protein to exhibit a range of biological functions, in tissue remodelling and mucosal immune defences in teleost ontogeny.
Lange S. - One of the best experts on this subject based on the ideXlab platform.
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Extracellular Vesicles and Post-Translational Protein Deimination Signatures in Mollusca—The Blue Mussel ( Mytilus edulis ), Soft Shell Clam ( Mya arenaria ), Eastern Oyster ( Crassostrea virginica ) and Atlantic Jacknife Clam ( Ensis leei )
'MDPI AG', 2020Co-Authors: Bowden, Timothy J., Kraev Igor, Lange S.Abstract:Oysters and clams are important for food security and of commercial value worldwide. They are affected by anthropogenic changes and opportunistic pathogens and can be indicators of changes in ocean environments. Therefore, studies into biomarker discovery are of considerable value. This study aimed at assessing extracellular vesicle (EV) signatures and post-translational Protein deimination profiles of hemolymph from four commercially valuable Mollusca species, the blue mussel (Mytilus edulis), soft shell clam (Mya arenaria), Eastern oyster (Crassostrea virginica), and Atlantic jacknife clam (Ensis leei). EVs form part of cellular communication by transporting Protein and genetic cargo and play roles in immunity and host−pathogen interactions. Protein deimination is a post-translational modification caused by peptidylarginine deiminases (PADs), and can facilitate Protein Moonlighting in health and disease. The current study identified hemolymph-EV profiles in the four Mollusca species, revealing some species differences. Deiminated Protein candidates differed in hemolymph between the species, with some common targets between all four species (e.g., histone H3 and H4, actin, and GAPDH), while other hits were species-specific; in blue mussel these included heavy metal binding Protein, heat shock Proteins 60 and 90, 2-phospho-D-glycerate hydrolyase, GTP cyclohydrolase feedback regulatory Protein, sodium/potassium-transporting ATPase, and fibrinogen domain containing Protein. In soft shell clam specific deimination hits included dynein, MCM3-associated Protein, and SCRN. In Eastern oyster specific deimination hits included muscle LIM Protein, beta-1,3-glucan-binding Protein, myosin heavy chain, thaumatin-like Protein, vWFA domain-containing Protein, BTB domain-containing Protein, amylase, and beta-catenin. Deiminated Proteins specific to Atlantic jackknife clam included nacre c1q domain-containing Protein and PDZ domain-containing Protein In addition, some Proteins were common as deiminated targets between two or three of the Bivalvia species under study (e.g., EP Protein, C1q domain containing Protein, histone H2B, tubulin, elongation factor 1-alpha, dominin, extracellular superoxide dismutase). Protein interaction network analysis for the deiminated Protein hits revealed major pathways relevant for immunity and metabolism, providing novel insights into post-translational regulation via deimination. The study contributes to EV characterization in diverse taxa and understanding of roles for PAD-mediated regulation of immune and metabolic pathways throughout phylogeny
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Post-translational Protein Deimination Signatures and Extracellular Vesicles (EVs) in the Atlantic Horseshoe Crab (Limulus polyphemus)
'Elsevier BV', 2020Co-Authors: Lange S., Bowden T.j.Abstract:The horseshoe crab is a living fossil and a species of marine arthropod with unusual immune system properties which are also exploited commercially. Given its ancient status dating to the Ordovician period (450 million years ago), its standing in phylogeny and unusual immunological characteristics, the horseshoe crab may hold valuable information for comparative immunology studies. Peptidylarginine deiminases (PADs) are calcium dependent enzymes that are phylogenetically conserved and cause Protein deimination via conversion of arginine to citrulline. This post-translational modification can lead to structural and functional Protein changes contributing to Protein Moonlighting in health and disease. PAD-mediated regulation of extracellular vesicle (EV) release, a critical component of cellular communication, has furthermore been identified to be a phylogenetically conserved mechanism. PADs, Protein deimination and EVs have hitherto not been studied in the horseshoe crab and were assessed in the current study. Horseshoe crab haemolymph serum-EVs were found to be a poly-dispersed population in the 20-400 nm size range, with the majority of EVs falling within 40-123 nm. Key immune Proteins were identified to be post-translationally deiminated in horseshoe crab haemolymph serum, providing insights into Protein Moonlighting function of Limulus and phylogenetically conserved immune Proteins. KEGG (Kyoto encyclopaedia of genes and genomes) and GO (gene ontology) enrichment analysis of deiminated Proteins identified in Limulus revealed KEGG pathways relating to complement and coagulation pathways, Staphylococcus aureus infection, glycolysis/gluconeogenesis and carbon metabolism, while GO pathways of biological and molecular pathways related to a range of immune and metabolic functions, as well as developmental processes. The characterisation of EVs, and post-translational deimination signatures, revealed here in horseshoe crab, contributes to current understanding of Protein Moonlighting functions and EV-mediated communication in this ancient arthropod and throughout phylogeny
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Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle- specific Signatures Relating to Immunity, Metabolic Function and Gene Regulation
'Frontiers Media SA', 2020Co-Authors: Lange S., Criscitiello M.f., Petersen L.h.Abstract:Alligators are crocodilians and among few species which endured the Cretaceous–Paleogene extinction event. With long life spans, low metabolic rates, unusual immunological characteristics and cancer resistance, crocodilians may hold information for molecular pathways underlying such physiological traits. Peptidylarginine deiminases (PADs) are a group of calcium-activated enzymes that cause post-translational Protein deimination/citrullination in a range of target Proteins contributing to Protein Moonlighting functions in health and disease. PADs are phylogenetically conserved and are also a key regulator of extracellular vesicle (EV) release; a critical part of cellular communication. As little is known about PAD-mediated mechanisms in reptile immunology, this study was aimed at profiling EVs and Protein deimination in Alligator mississippiensis. Alligator plasma-EVs were found to be poly-dispersed in a 50-400 nm size range. Key immune, metabolic and gene regulatory Proteins were identified to be post-translationally deiminated in plasma and plasma-EVs, with some overlapping hits, while some were unique to either plasma or plasma-EVs. In whole plasma, 112 target Proteins were identified to be deiminated, while 77 Proteins were found as deiminated Protein hits in plasma-EVs, whereof 31 were specific for EVs only, including Proteins specific for gene regulatory functions (e.g. histones). GO and KEGG enrichment analysis revealed KEGG pathways specific to deiminated Proteins in whole plasma related to adipocytokine signalling, while KEGG pathways of deiminated Proteins specific to EVs included ribosome, biosynthesis of amino acids and glycolysis/gluconeogenesis pathways as well as core histones. This highlights roles for EV-mediated export of deiminated Protein cargo with roles in metabolism and gene regulation, also related to cancer. The identification of post-translational deimination and EV-mediated communication in alligator plasma revealed here, contributes to current understanding of Protein Moonlighting functions and EV-mediated communication in these ancient reptiles, providing novel insight into their unusual immune systems and physiological traits. In addition our findings may shed light on pathways underlying cancer-resistance, anti-viral and anti-bacterial resistance, with translatable value to human pathologies
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Extracellular Vesicles and Post-translational Protein Deimination Signatures in Haemolymph of the American Lobster (Homarus americanus)
'Elsevier BV', 2020Co-Authors: Lange S., Bowden T.j.Abstract:The American lobster (Homarus americanus) is a commercially important crustacean with an unusual long life span up to 100 years and a comparative animal model of longevity. Therefore, research into its immune system and physiology is of considerable importance both for industry and comparative immunology studies. Peptidylarginine deiminases (PADs) are a phylogenetically conserved enzyme family that catalyses post-translational Protein deimination via the conversion of arginine to citrulline. This can lead to structural and functional Protein changes, sometimes contributing to Protein Moonlighting, in health and disease. PADs also regulate the cellular release of extracellular vesicles (EVs), which is an important part of cellular communication, both in normal physiology and in immune responses. Hitherto, studies on EV in Crustacea are limited and neither PADs nor associated Protein deimination have been studied in a Crustacean species. The current study assessed EV and deimination signatures in haemolymph of the American lobster. Lobster EVs were found to be a poly-dispersed population in the 10-500 nm size range, with the majority of smaller EVs, which fell within 22-115 nm. In lobster haemolymph, 9 key immune and metabolic Proteins were identified to be post-translationally deiminated, while further 41 deiminated Protein hits were identified when searching against a Crustacean database. KEGG (Kyoto encyclopedia of genes and genomes) and GO (gene ontology) enrichment analysis of these deiminated Proteins revealed KEGG and GO pathways relating to a number of immune, including anti-pathogenic (viral, bacterial, fungal) and host-pathogen interactions, as well as metabolic pathways, regulation of vesicle and exosome release, mitochondrial function, ATP generation, gene regulation, telomerase homeostasis and developmental processes. The characterisation of EVs, and post-translational deimination signatures, reported in lobster in the current study, and the first time in Crustacea, provides insights into Protein Moonlighting functions of both species-specific and phylogenetically conserved Proteins and EV-mediated communication in this long-lived crustacean. The current study furthermore lays foundation for novel biomarker discovery for lobster aquaculture
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Deiminated Proteins and Extracellular Vesicles - Novel Serum Biomarkers in Whales and Orca
'Elsevier BV', 2020Co-Authors: Lange S., Uysal Onganer P., Magnadóttir B., Hayes P.m.Abstract:Peptidylarginine deiminases (PADs) are a family of phylogenetically conserved calcium-dependent enzymes which cause post-translational Protein deimination. This can result in neo-epitope generation, affect gene regulation and allow for Protein Moonlighting via functional and structural changes in target Proteins. Extracellular vesicles (EVs) carry cargo Proteins and genetic material and are released from cells as part of cellular communication. EVs are found in most body fluids where they can be useful biomarkers for assessment of health status. Here, serum-derived EVs were profiled, and post-translationally deiminated Proteins and EV-related microRNAs are described in 5 ceataceans: minke whale, fin whale, humpback whale, Cuvier’s beaked whale and orca. EV-serum profiles were assessed by transmission electron microscopy and nanoparticle tracking analysis. EV profiles varied between the 5 species and were identified to contain deiminated Proteins and selected key inflammatory and metabolic microRNAs. A range of Proteins, critical for immune responses and metabolism were identified to be deiminated in cetacean sera, with some shared KEGG pathways of deiminated Proteins relating to immunity and physiology, while some KEGG pathways were species-specific. This is the first study to characterise and profile EVs and to report deiminated Proteins and putative effects of Protein-Protein interaction networks via such post-translationald deimination in cetaceans, revealing key immune and metabolic factors to undergo this post-translational modification. Deiminated Proteins and EVs profiles may possibly be developed as new biomarkers for assessing health status of sea mammals
Andrew J. Martin - One of the best experts on this subject based on the ideXlab platform.
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Protein Moonlighting: a new factor in biology and medicine
Biochemical Society transactions, 2014Co-Authors: Brian E Henderson, Andrew J. MartinAbstract:The phenomenon of Protein Moonlighting was discovered in the 1980s and 1990s, and the current definition of what constitutes a Moonlighting Protein was provided at the end of the 1990s. Since this time, several hundred Moonlighting Proteins have been identified in all three domains of life, and the rate of discovery is accelerating as the importance of Protein Moonlighting in biology and medicine becomes apparent. The recent re-evaluation of the number of Protein-coding genes in the human genome (approximately 19000) is one reason for believing that Protein Moonlighting may be a more general phenomenon than the current number of Moonlighting Proteins would suggest, and preliminary studies of the proportion of Proteins that moonlight would concur with this hypothesis. Protein Moonlighting could be one way of explaining the seemingly small number of Proteins that are encoded in the human genome. It is emerging that Moonlighting Proteins can exhibit novel biological functions, thus extending the range of the human functional proteome. The several hundred Moonlighting Proteins so far discovered play important roles in many aspects of biology. For example, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), heat-shock Protein 60 (Hsp60) and tRNA synthetases play a wide range of biological roles in eukaryotic cells, and a growing number of eukaryotic Moonlighting Proteins are recognized to play important roles in physiological processes such as sperm capacitation, implantation, immune regulation in pregnancy, blood coagulation, vascular regeneration and control of inflammation. The dark side of Protein Moonlighting finds a range of Moonlighting Proteins playing roles in various human diseases including cancer, cardiovascular disease, HIV and cystic fibrosis. However, some Moonlighting Proteins are being tested for their therapeutic potential, including immunoglobulin heavy-chain-binding Protein (BiP), for rheumatoid arthritis, and Hsp90 for wound healing. In addition, it has emerged over the last 20 years that a large number of bacterial Moonlighting Proteins play important roles in bacteria–host interactions as virulence factors and are therefore potential therapeutic targets in bacterial infections. So as we progress in the 21st Century, it is likely that Moonlighting Proteins will be seen to play an increasingly important role in biology and medicine. It is hoped that some of the major unanswered questions, such as the mechanism of evolution of Protein Moonlighting, the structural biology of Moonlighting Proteins and their role in the systems biology of cellular systems can be addressed during this period.
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Structural biology of Moonlighting: lessons from antibodies.
Biochemical Society transactions, 2014Co-Authors: Andrew J. MartinAbstract:Protein Moonlighting is the property of a number of Proteins to have more than one function. However, the definition of Moonlighting is somewhat imprecise with different interpretations of the phenomenon. True Moonlighting occurs when an individual evolutionary Protein domain has one well-accepted role and a secondary unrelated function. The 'function' of a Protein domain can be defined at different levels. For example, although the function of an antibody variable fragment (Fv) could be described as 'binding', a more detailed definition would also specify the molecule to which the Fv region binds. Using this detailed definition, antibodies as a family are consummate moonlighters. However, individual antibodies do not moonlight; the multiple functions they exhibit (first binding a molecule and second triggering the immune response) are encoded in different domains and, in any case, are related in the sense that they are a part of what an antibody needs to do. Nonetheless, antibodies provide interesting lessons on the ability of Proteins to evolve binding functions. Remarkably similar antibody sequences can bind completely different antigens, suggesting that evolving the ability to bind a Protein can result from very subtle sequence changes.
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Bacterial Moonlighting Proteins and bacterial virulence.
Current topics in microbiology and immunology, 2011Co-Authors: Brian Henderson, Andrew J. MartinAbstract:Implicit in the central dogma is the hypothesis that each Protein gene product has but one function. However, over the past decade, it has become clear that many Proteins have one or more unique functions, over-and-above the principal biological action of the specific Protein. This phenomenon is now known as Protein Moonlighting and many well-known Proteins such as metabolic enzymes and molecular chaperones are now recognised as Moonlighting Proteins. A growing number of bacterial species are being found to have Moonlighting Proteins and the Moonlighting activities of such Proteins can contribute to bacterial virulence behaviour. The glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPD) and enolase, and the cell stress Proteins: chaperonin 60, Hsp70 and peptidyl prolyl isomerase, are among the most common of the bacterial Moonlighting Proteins which play a role in bacterial virulence. Moonlighting activities include adhesion and modulation of cell signalling processes. It is likely that only the tip of the bacterial Moonlighting iceberg has been sighted and the next decade will bring with it many new discoveries of bacterial Moonlighting Proteins with a role in bacterial virulence.
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bacterial virulence in the moonlight multitasking bacterial Moonlighting Proteins are virulence determinants in infectious disease
Infection and Immunity, 2011Co-Authors: Brian E Henderson, Andrew J. MartinAbstract:Men may not be able to multitask, but it is emerging that Proteins can. This capacity of Proteins to exhibit more than one function is termed Protein Moonlighting, and, surprisingly, many highly conserved Proteins involved in metabolic regulation or the cell stress response have a range of additional biological actions which are involved in bacterial virulence. This review highlights the multiple roles exhibited by a range of bacterial Proteins, such as glycolytic and other metabolic enzymes and molecular chaperones, and the role that such Moonlighting activity plays in the virulence characteristics of a number of important human pathogens, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Helicobacter pylori, and Mycobacterium tuberculosis.
Igor Kraev - One of the best experts on this subject based on the ideXlab platform.
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Extracellular Vesicles and Post-Translational Protein Deimination Signatures in Mollusca-The Blue Mussel (Mytilus edulis), Soft Shell Clam (Mya arenaria), Eastern Oyster (Crassostrea virginica) and Atlantic Jacknife Clam (Ensis leei).
Biology, 2020Co-Authors: Timothy J. Bowden, Igor Kraev, Sigrun LangeAbstract:Oysters and clams are important for food security and of commercial value worldwide. They are affected by anthropogenic changes and opportunistic pathogens and can be indicators of changes in ocean environments. Therefore, studies into biomarker discovery are of considerable value. This study aimed at assessing extracellular vesicle (EV) signatures and post-translational Protein deimination profiles of hemolymph from four commercially valuable Mollusca species, the blue mussel (Mytilus edulis), soft shell clam (Mya arenaria), Eastern oyster (Crassostrea virginica), and Atlantic jacknife clam (Ensis leei). EVs form part of cellular communication by transporting Protein and genetic cargo and play roles in immunity and host–pathogen interactions. Protein deimination is a post-translational modification caused by peptidylarginine deiminases (PADs), and can facilitate Protein Moonlighting in health and disease. The current study identified hemolymph-EV profiles in the four Mollusca species, revealing some species differences. Deiminated Protein candidates differed in hemolymph between the species, with some common targets between all four species (e.g., histone H3 and H4, actin, and GAPDH), while other hits were species-specific; in blue mussel these included heavy metal binding Protein, heat shock Proteins 60 and 90, 2-phospho-D-glycerate hydrolyase, GTP cyclohydrolase feedback regulatory Protein, sodium/potassium-transporting ATPase, and fibrinogen domain containing Protein. In soft shell clam specific deimination hits included dynein, MCM3-associated Protein, and SCRN. In Eastern oyster specific deimination hits included muscle LIM Protein, beta-1,3-glucan-binding Protein, myosin heavy chain, thaumatin-like Protein, vWFA domain-containing Protein, BTB domain-containing Protein, amylase, and beta-catenin. Deiminated Proteins specific to Atlantic jackknife clam included nacre c1q domain-containing Protein and PDZ domain-containing Protein In addition, some Proteins were common as deiminated targets between two or three of the Bivalvia species under study (e.g., EP Protein, C1q domain containing Protein, histone H2B, tubulin, elongation factor 1-alpha, dominin, extracellular superoxide dismutase). Protein interaction network analysis for the deiminated Protein hits revealed major pathways relevant for immunity and metabolism, providing novel insights into post-translational regulation via deimination. The study contributes to EV characterization in diverse taxa and understanding of roles for PAD-mediated regulation of immune and metabolic pathways throughout phylogeny.
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deiminated Proteins in extracellular vesicles and serum of llama lama glama novel insights into camelid immunity
Molecular Immunology, 2020Co-Authors: Michael F Criscitiello, Igor Kraev, Sigrun LangeAbstract:Peptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which post-translationally convert arginine into citrulline in target Proteins in an irreversible manner, causing functional and structural changes in target Proteins. Protein deimination causes generation of neo-epitopes, affects gene regulation and also allows for Protein Moonlighting. Furthermore, PADs have been found to be a phylogenetically conserved regulator for extracellular vesicle (EVs) release. EVs are found in most body fluids and participate in cellular communication via transfer of cargo Proteins and genetic material. In this study, post-translationally deiminated Proteins in serum and serum-EVs are described for the first time in camelids, using the llama (Lama glama L. 1758) as a model animal. We report a poly-dispersed population of llama serum EVs, positive for phylogenetically conserved EV-specific markers and characterised by TEM. In serum, 103 deiminated Proteins were overall identified, including key immune and metabolic mediators including complement components, immunoglobulin-based nanobodies, adiponectin and heat shock Proteins. In serum, 60 deiminated Proteins were identified that were not in EVs, and 25 deiminated Proteins were found to be unique to EVs, with 43 shared deiminated Protein hits between both serum and EVs. Deiminated histone H3, a marker of neutrophil extracellular trap formation, was also detected in llama serum. PAD homologues were identified in llama serum by Western blotting, via cross reaction with human PAD antibodies, and detected at an expected 70 kDa size. This is the first report of deiminated Proteins in serum and EVs of a camelid species, highlighting a hitherto unrecognized post-translational modification in key immune and metabolic Proteins in camelids, which may be translatable to and inform a range of human metabolic and inflammatory pathologies.
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Complement component C4-like Protein in Atlantic cod (Gadus morhua L.) - Detection in ontogeny and identification of post-translational deimination in serum and extracellular vesicles.
Developmental and comparative immunology, 2019Co-Authors: Sigrun Lange, Bergljót Magnadóttir, Igor Kraev, Alister W. DoddsAbstract:The complement system is a critical part of teleost immune defences, with complement component C4 forming part of the classical and lectin pathways. Cod C4-like Protein was isolated from plasma, specific antibodies generated and C4-like Protein was assessed in cod sera, mucus and in extracellular vesicles (EVs) from serum and mucus. Higher levels of C4-like Protein were detected in serum- than mucus-derived EVs. Post-translational deimination, caused by conversion of arginine into citrulline, can affect Protein structure and function. Here we detected deiminated forms of C4-like Protein in cod serum and at lower levels in mucus. C4-like Protein was also found in deiminated form at low levels in EVs from both serum and mucus. C4-like Protein was assessed by immunohistochemistry in cod larvae and detected in a range of organs including in liver, kidney, gut, muscle, skin and mucus, as well as in neuronal tissues of the brain, spinal cord and eye. This abundance of C4-like Protein during early development may indicate roles in tissue remodelling, in addition to immune defences. The presence of deiminated C4-like Protein in serum and mucosa, as well as in EVs, may suggest C4 Protein Moonlighting via post-translational deimination.
Brian E Henderson - One of the best experts on this subject based on the ideXlab platform.
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An overview of Protein Moonlighting in bacterial infection
Biochemical Society transactions, 2014Co-Authors: Brian E HendersonAbstract:We are rapidly returning to a world in which bacterial infections are a major health issue. Pathogenic bacteria are able to colonize and cause pathology due to the possession of virulence factors such as adhesins, invasins, evasins and toxins. These are generally specifically evolved Proteins with selective actions. It is, therefore, surprising that most human bacterial pathogens employ Moonlighting Proteins as virulence factors. Currently, >90 bacterial species employ one or more Moonlighting Protein families to aid colonization and induce disease. These organisms employ 90 Moonlighting bacterial Protein families and these include enzymes of the glycolytic pathway, tricarboxylic acid (TCA) cycle, hexosemonophosphate shunt, glyoxylate cycle and a range of other metabolic enzymes, proteases, transporters and, also, molecular chaperones and Protein-folding catalysts. These Proteins have homologues in eukaryotes and only a proportion of the Moonlighting Proteins employed are solely bacterial in origin. Bacterial Moonlighting Proteins can be divided into those with single Moonlighting functions and those with multiple additional biological actions. These Proteins contribute significantly to the population of virulence factors employed by bacteria and some are obvious therapeutic targets. Where examined, bacterial Moonlighting Proteins bind to target ligands with high affinity. A major puzzle is the evolutionary mechanism(s) responsible for bacterial Protein Moonlighting and a growing number of highly homologous bacterial Moonlighting Proteins exhibit widely different Moonlighting actions, suggesting a lack in our understanding of the mechanism of evolution of Protein active sites.
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Protein Moonlighting: a new factor in biology and medicine
Biochemical Society transactions, 2014Co-Authors: Brian E Henderson, Andrew J. MartinAbstract:The phenomenon of Protein Moonlighting was discovered in the 1980s and 1990s, and the current definition of what constitutes a Moonlighting Protein was provided at the end of the 1990s. Since this time, several hundred Moonlighting Proteins have been identified in all three domains of life, and the rate of discovery is accelerating as the importance of Protein Moonlighting in biology and medicine becomes apparent. The recent re-evaluation of the number of Protein-coding genes in the human genome (approximately 19000) is one reason for believing that Protein Moonlighting may be a more general phenomenon than the current number of Moonlighting Proteins would suggest, and preliminary studies of the proportion of Proteins that moonlight would concur with this hypothesis. Protein Moonlighting could be one way of explaining the seemingly small number of Proteins that are encoded in the human genome. It is emerging that Moonlighting Proteins can exhibit novel biological functions, thus extending the range of the human functional proteome. The several hundred Moonlighting Proteins so far discovered play important roles in many aspects of biology. For example, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), heat-shock Protein 60 (Hsp60) and tRNA synthetases play a wide range of biological roles in eukaryotic cells, and a growing number of eukaryotic Moonlighting Proteins are recognized to play important roles in physiological processes such as sperm capacitation, implantation, immune regulation in pregnancy, blood coagulation, vascular regeneration and control of inflammation. The dark side of Protein Moonlighting finds a range of Moonlighting Proteins playing roles in various human diseases including cancer, cardiovascular disease, HIV and cystic fibrosis. However, some Moonlighting Proteins are being tested for their therapeutic potential, including immunoglobulin heavy-chain-binding Protein (BiP), for rheumatoid arthritis, and Hsp90 for wound healing. In addition, it has emerged over the last 20 years that a large number of bacterial Moonlighting Proteins play important roles in bacteria–host interactions as virulence factors and are therefore potential therapeutic targets in bacterial infections. So as we progress in the 21st Century, it is likely that Moonlighting Proteins will be seen to play an increasingly important role in biology and medicine. It is hoped that some of the major unanswered questions, such as the mechanism of evolution of Protein Moonlighting, the structural biology of Moonlighting Proteins and their role in the systems biology of cellular systems can be addressed during this period.
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bacterial virulence in the moonlight multitasking bacterial Moonlighting Proteins are virulence determinants in infectious disease
Infection and Immunity, 2011Co-Authors: Brian E Henderson, Andrew J. MartinAbstract:Men may not be able to multitask, but it is emerging that Proteins can. This capacity of Proteins to exhibit more than one function is termed Protein Moonlighting, and, surprisingly, many highly conserved Proteins involved in metabolic regulation or the cell stress response have a range of additional biological actions which are involved in bacterial virulence. This review highlights the multiple roles exhibited by a range of bacterial Proteins, such as glycolytic and other metabolic enzymes and molecular chaperones, and the role that such Moonlighting activity plays in the virulence characteristics of a number of important human pathogens, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Helicobacter pylori, and Mycobacterium tuberculosis.
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Multiple Moonlighting functions of mycobacterial molecular chaperones
Tuberculosis (Edinburgh Scotland), 2010Co-Authors: Brian E Henderson, Peter A. Lund, Anthony R.m. CoatesAbstract:Molecular chaperones and Protein folding catalysts are normally thought of as intracellular Proteins involved in Protein folding quality control. However, in the mycobacteria there is increasing evidence to support the hypothesis that molecular chaperones are also secreted intercellular signalling molecules or can control actions at the cell wall or indeed control the composition of the cell wall. The most recent evidence for Protein Moonlighting in the mycobacteria is the report that chaperonin 60.2 of Mycobacterium tuberculosis is important in the key event in tuberculosis - the entry of the bacterium into the macrophage. This brief overview highlights the potential importance of the Moonlighting functions of molecular chaperones in the biology and pathobiology of the mycobacteria.
