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1دورية أكاديمية
المؤلفون: Krammer, Eva-Maria, Bridot, Clarisse, Serna, Sonia, Echeverria, Begoña, Semwal, Shubham, Roubinet, Benoît, van Noort, Kim, Wilbers, Ruud H.P., Bourenkov, Gleb, de Ruyck, Jérôme, Landemarre, Ludovic, Reichardt, Niels, Bouckaert, Julie
المصدر: Journal of Biological Chemistry 299 (2023) 5 ; ISSN: 0021-9258
مصطلحات موضوعية: FimH, N-glycan, bacterial adhesion, cooperativity, core fucose, crystal structure, kinetics, multivalency, oligomannose-3, oligomannose-6, paucimannose
الوصف: The FimH type-1 fimbrial adhesin allows pathogenic Escherichia coli to adhere to glycoproteins in the epithelial linings of human bladder and intestinal tract, by using multiple fimbriae simultaneously. Pauci- and high-mannose type N-glycans are natural FimH receptors on those glycoproteins. Oligomannose-3 and oligomannose-5 bind with the highest affinity to FimH by using the same Manα1,3Man branch. Oligomannose-6 is generated from oligomannose-5 in the next step of the biogenesis of high-mannose N-glycans, by the transfer of a mannose in α1,2-linkage onto this branch. Using serial crystallography and by measuring the kinetics of binding, we demonstrate that shielding the high-affinity epitope drives the binding of multiple FimH molecules. First, we profiled FimH glycan binding on a microarray containing paucimannosidic N-glycans and in a FimH LEctPROFILE assay. To make the transition to oligomannose-6, we measured the kinetics of FimH binding using paucimannosidic N-glycans, glycoproteins and all four α-dimannosides conjugated to bovine serum albumin. Equimolar mixed interfaces of the dimannosides present in oligomannose-6 and molecular dynamics simulations suggest a positive cooperativity in the bivalent binding of Manα1,3Manα1 and Manα1,6Manα1 dimannosides. The binding of core α1,6-fucosylated oligomannose-3 in cocrystals of FimH is monovalent but interestingly the GlcNAc1—Fuc moiety retains highly flexibility. In cocrystals with oligomannose-6, two FimH bacterial adhesins bind the Manα1,3Manα1 and Manα1,6Manα1 endings of the second trimannose core (A-4′-B). This cooperative switch towards bivalent binding appears sustainable beyond a molar excess of oligomannose-6. Our findings provide important novel structural insights for the design of multivalent FimH antagonists that bind with positive cooperativity.
وصف الملف: application/pdf
العلاقة: https://edepot.wur.nl/629767Test; https://research.wur.nl/en/publications/structural-insights-into-a-cooperative-switch-between-one-and-twoTest
الإتاحة: https://doi.org/10.1016/j.jbc.2023.104627Test
https://research.wur.nl/en/publications/structural-insights-into-a-cooperative-switch-between-one-and-twoTest -
2دورية أكاديمية
المصدر: Frontiers in Plant Science 13 (2022) ; ISSN: 1664-462X
مصطلحات موضوعية: Life Science
الوصف: Glycoproteins are the dominant category among approved biopharmaceuticals, indicating their importance as therapeutic proteins. Glycoproteins are decorated with carbohydrate structures (or glycans) in a process called glycosylation. Glycosylation is a post-translational modification that is present in all kingdoms of life, albeit with differences in core modifications, terminal glycan structures, and incorporation of different sugar residues. Glycans play pivotal roles in many biological processes and can impact the efficacy of therapeutic glycoproteins. The majority of biopharmaceuticals are based on human glycoproteins, but non-human glycoproteins, originating from for instance parasitic worms (helminths), form an untapped pool of potential therapeutics for immune-related diseases and vaccine candidates. The production of sufficient quantities of correctly glycosylated putative therapeutic helminth proteins is often challenging and requires extensive engineering of the glycosylation pathway. Therefore, a flexible glycoprotein production system is required that allows straightforward introduction of heterologous glycosylation machinery composed of glycosyltransferases and glycosidases to obtain desired glycan structures. The glycome of plants creates an ideal starting point for N- and O-glyco-engineering of helminth glycans. Plants are also tolerant toward the introduction of heterologous glycosylation enzymes as well as the obtained glycans. Thus, a potent production platform emerges that enables the production of recombinant helminth proteins with unusual glycans. In this review, we discuss recent advances in plant glyco-engineering of potentially therapeutic helminth glycoproteins, challenges and their future prospects.
وصف الملف: application/pdf
العلاقة: https://edepot.wur.nl/569650Test; https://research.wur.nl/en/publications/glyco-engineering-plants-to-produce-helminth-glycoproteins-as-proTest
الإتاحة: https://doi.org/10.3389/fpls.2022.882835Test
https://research.wur.nl/en/publications/glyco-engineering-plants-to-produce-helminth-glycoproteins-as-proTest -
3دورية أكاديمية
المؤلفون: van der Zande, Hendrik J.P., Gonzalez, Michael A., Ruiter, Karin, Wilbers, Ruud H.P., García‐Tardón, Noemí, van Huizen, Mariska, van Noort, Kim, Pelgrom, Leonard R., Lambooij, Joost M., Zawistowska‐Deniziak, Anna, Otto, Frank, Ozir‐Fazalalikhan, Arifa, van Willigen, Danny, Welling, Mick, Poles, Jordan, Leeuwen, Fijs, Hokke, Cornelis H., Schots, Arjen, Yazdanbakhsh, Maria, Loke, P., Guigas, Bruno
المصدر: FASEB Journal 35 (2021) 2 ; ISSN: 0892-6638
مصطلحات موضوعية: helminths, immunometabolism, insulin sensitivity, macrophages, type 2 immunity
الوصف: Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta‐inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet, a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega‐1 (ω1), one of the major S mansoni immunomodulatory glycoproteins, on metabolic homeostasis. We show that treatment of obese mice with plant‐produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass, and improved systemic insulin sensitivity and glucose tolerance in a time‐ and dose‐dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils, and alternatively activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6‐deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole‐body energy expenditure, an effect also occurring in leptin receptor‐deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole‐body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6‐independent mechanism.
وصف الملف: application/pdf
العلاقة: https://edepot.wur.nl/539952Test; https://research.wur.nl/en/publications/the-helminth-glycoprotein-omega1-improves-metabolic-homeostasis-iTest
الإتاحة: https://doi.org/10.1096/fj.202001973RTest
https://research.wur.nl/en/publications/the-helminth-glycoprotein-omega1-improves-metabolic-homeostasis-iTest -
4دورية أكاديمية
المؤلفون: van Noort, Kim, Nguyen, Dieu Linh, Kriechbaumer, Verena, Hawes, Chris, Hokke, Cornelis H., Schots, Arjen, Wilbers, Ruud H.P.
المصدر: Scientific Reports 11 (2021) 1 ; ISSN: 2045-2322
مصطلحات موضوعية: Life Science
الوصف: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
وصف الملف: application/pdf
العلاقة: https://edepot.wur.nl/543145Test; https://research.wur.nl/en/publications/correction-functional-characterization-of-schistosoma-mansoni-fucTest
الإتاحة: https://doi.org/10.1038/s41598-021-83766-0Test
https://research.wur.nl/en/publications/correction-functional-characterization-of-schistosoma-mansoni-fucTest -
5دورية أكاديمية
المؤلفون: Alvisi, Nicolò, van Noort, Kim, Dwiani, Sarlita, Geschiere, Nathan, Sukarta, Octavina, Varossieau, Koen, Nguyen, Dieu-Linh, Strasser, Richard, Hokke, Cornelis H., Schots, Arjen, Wilbers, Ruud H.P.
المصدر: Frontiers in Plant Science 12 (2021) ; ISSN: 1664-462X
مصطلحات موضوعية: ERP127155, LacdiNAc, N-glycosylation, Nicotiana benthamiana, PRJEB43212, glyco-engineering, β-hexosaminidases
الوصف: Secretions of parasitic worms (helminths) contain a wide collection of immunomodulatory glycoproteins with the potential to treat inflammatory disorders, like autoimmune diseases. Yet, the identification of single molecules that can be developed into novel biopharmaceuticals is hampered by the limited availability of native parasite-derived proteins. Recently, pioneering work has shown that helminth glycoproteins can be produced transiently in Nicotiana benthamiana plants while simultaneously mimicking their native helminth N-glycan composition by co-expression of desired glycosyltransferases. However, efficient “helminthization” of N-glycans in plants by glyco-engineering seems to be hampered by the undesired truncation of complex N-glycans by β-N-acetyl-hexosaminidases, in particular when aiming for the synthesis of N-glycans with antennary GalNAcβ1-4GlcNAc (LacdiNAc or LDN). In this study, we cloned novel β-hexosaminidase open reading frames from N. benthamiana and characterized the biochemical activity of these enzymes. We identified HEXO2 and HEXO3 as enzymes responsible for the cleavage of antennary GalNAc residues of N-glycans on the model helminth glycoprotein kappa-5. Furthermore, we reveal that each member of the HEXO family has a distinct specificity for N-glycan substrates, where HEXO2 has strict β-galactosaminidase activity, whereas HEXO3 cleaves both GlcNAc and GalNAc. The identification of HEXO2 and HEXO3 as major targets for LDN cleavage will enable a targeted genome editing approach to reduce undesired processing of these N-glycans. Effective knockout of these enzymes could allow the production of therapeutically relevant glycoproteins with tailor-made helminth N-glycans in plants.
وصف الملف: application/pdf
العلاقة: https://edepot.wur.nl/543833Test; https://research.wur.nl/en/publicationsTest/β-hexosaminidases-along-the-secretory-pathway-of-nicotiana-bentha
الإتاحة: https://doi.org/10.3389/fpls.2021.638454Test
https://research.wur.nl/en/publicationsTest/β-hexosaminidases-along-the-secretory-pathway-of-nicotiana-bentha -
6دورية أكاديمية
المؤلفون: Robakiewicz, Stefania, Bridot, Clarisse, Serna, Sonia, Gimeno, Ana, Echeverria, Begoña, Delgado, Sandra, de Ruyck, Jerome, Semwal, Shubham, Charro, Diego, Dansercoer, Ann, Verstraete, Kenneth, Azkargorta, Mikel, van Noort, Kim, Wilbers, Ruud H P, Savvides, Savvas N, Abrescia, Nicola G A, Arda, Ana, Reichardt, Niels C, Jiménez-Barbero, Jesús, Bouckaert, Julie
المساهمون: Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centro de Investigación Cooperativa en Biomateriales (CIC biomaGUNE), Center for Cooperative Research in Biosciences = Centro de Investigación cooperativa en biociencia (Derio, Biscay, Espagne) (CIC bioGUNE), VIB-UGent Center for Inflammation Research Gand, Belgique (IRC), VIB Belgium, Wageningen University and Research Wageningen (WUR), Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III Madrid (ISC)-ministerio de ciencia e innovacion
المصدر: ISSN: 0959-6658.
مصطلحات موضوعية: core fucose, IgM, Mannitou, N-glycan, paucimannosidic epitopes, [SDV]Life Sciences [q-bio]
الوصف: International audience ; Abstract Paucimannosidic glycans are restricted to the core structure [Man1–3GlcNAc2Fuc0–1] of N-glycans and are rarely found in mammalian tissues. Yet, especially [Man2-3GlcNAc2Fuc1] have been found significantly upregulated in tumors, including in colorectal and liver cancer. Mannitou IgM is a murine monoclonal antibody that was previously shown to recognize Man3GlcNAc2 with an almost exclusive selectivity. Here, we have sought the definition of the minimal glycan epitope of Mannitou IgM, initiated by screening on a newly designed paucimannosidic glycan microarray; among the best binders were Man3GlcNAc2 and its α1,6 core-fucosylated variant, Man3GlcNAc2Fuc1. Unexpectedly and in contrast to earlier findings, Man5GlcNAc2-type structures bind equally well and a large tolerance was observed for substitutions on the α1,6 arm. It was confirmed that any substitution on the single α1,3-linked mannose completely abolishes binding. Surface plasmon resonance for kinetic measurements of Mannitou IgM binding, either directly on the glycans or as presented on omega-1 and kappa-5 soluble egg antigens from the helminth parasite Schistosoma mansoni, showed submicromolar affinities. To characterize the epitope in greater and atomic detail, saturation transfer difference nuclear magnetic resonance spectroscopy was performed with the Mannitou antigen-binding fragment. The STD-NMR data demonstrated the strongest interactions with the aliphatic protons H1 and H2 of the α1–3-linked mannose and weaker imprints on its H3, H4 and H5 protons. In conclusion, Mannitou IgM binding requires a nonsubstituted α1,3-linked mannose branch of paucimannose also on proteins, making it a highly specific tool for the distinction of concurrent human tumor-associated carbohydrate antigens.
العلاقة: hal-03283666; https://hal.univ-lille.fr/hal-03283666Test; https://hal.univ-lille.fr/hal-03283666v2/documentTest; https://hal.univ-lille.fr/hal-03283666v2/file/P21.02%20GLYCO-2021-00007.R1_Proof_hi.pdfTest
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7دورية أكاديمية
المؤلفون: Zande, Hendrik J.P., Gonzalez, Michael A., Ruiter, Karin, Wilbers, Ruud H.P., García‐Tardón, Noemí, Huizen, Mariska, Noort, Kim, Pelgrom, Leonard R., Lambooij, Joost M., Zawistowska‐Deniziak, Anna, Otto, Frank, Ozir‐Fazalalikhan, Arifa, Willigen, Danny, Welling, Mick, Poles, Jordan, Leeuwen, Fijs, Hokke, Cornelis H., Schots, Arjen, Yazdanbakhsh, Maria, Loke, P'ng, Guigas, Bruno
المساهمون: ZonMw, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, U.S. Department of Defense
المصدر: The FASEB Journal ; volume 35, issue 2 ; ISSN 0892-6638 1530-6860
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8دورية أكاديمية
المؤلفون: van Noort, Kim, Nguyen, Dieu‑Linh, Kriechbaumer, Verena, Hawes, Chris, Hokke, Cornelis H., Schots, Arjen, Wilbers, Ruud H. P.
المصدر: Scientific Reports ; volume 11, issue 1 ; ISSN 2045-2322
مصطلحات موضوعية: Multidisciplinary
الوصف: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
الإتاحة: https://doi.org/10.1038/s41598-021-83766-0Test
https://www.nature.com/articles/s41598-021-83766-0.pdfTest
https://www.nature.com/articles/s41598-021-83766-0Test -
9دورية أكاديمية
المؤلفون: Van Noort, Kim, Nguyen, Dieu-Linh, Kriechbaumer, Verena, Hawes, Chris, Hokke, Cornelis H., Schots, Arjen, Wilbers, Ruud H.P.
المصدر: Scientific Reports 10 (2020) ; ISSN: 2045-2322
مصطلحات موضوعية: Life Science
الوصف: Helminth parasites secrete a wide variety of immunomodulatory proteins and lipids to dampen host immune responses. Many of these immunomodulatory compounds are modified with complex sugar structures (or glycans), which play an important role at the host–parasite interface. As an example, the human blood fluke Schistosoma mansoni produces highly fucosylated glycan structures on glycoproteins and glycolipids. Up to 20 different S. mansoni fucosyltransferase (SmFucT) genes can be found in genome databases, but thus far only one enzyme has been functionally characterized. To unravel the synthesis of highly fucosylated N-glycans by S. mansoni, we examined the ability of ten selected SmFucTs to modify N-glycans upon transient expression in Nicotiana benthamiana plants. All enzymes were localized in the plant Golgi apparatus, which allowed us to identify the SmFucTs involved in core fucosylation and the synthesis of complex antennary glycan motifs. This knowledge provides a starting point for investigations into the role of specific fucosylated glycan motifs of schistosomes in parasite-host interactions. The functionally characterized SmFucTs can also be applied to synthesize complex N-glycan structures on recombinant proteins to study their contribution to immunomodulation. Furthermore, this plant expression system will fuel the development of helminth glycoproteins for pharmaceutical applications or novel anti-helminth vaccines.
وصف الملف: application/pdf
العلاقة: https://edepot.wur.nl/533573Test; https://research.wur.nl/en/publications/functional-characterization-of-schistosoma-mansoni-fucosyltransfeTest
الإتاحة: https://doi.org/10.1038/s41598-020-74485-zTest
https://research.wur.nl/en/publications/functional-characterization-of-schistosoma-mansoni-fucosyltransfeTest -
10دورية أكاديمية
المؤلفون: Noort, Kim van, Nguyen, Dieu-Linh, Kriechbaumer, Verena, Hawes, Chris, Hokke, Cornelis H., Schots, Arjen, Wilbers, Ruud H.P.
الوصف: Helminth parasites secrete a wide variety of immunomodulatory proteins and lipids to dampen host immune responses. Many of these immunomodulatory compounds are modified with complex sugar structures (or glycans), which play an important role at the host–parasite interface. As an example, the human blood fluke Schistosoma mansoni produces highly fucosylated glycan structures on glycoproteins and glycolipids. Up to 20 different S. mansoni fucosyltransferase (SmFucT) genes can be found in genome databases, but thus far only one enzyme has been functionally characterized. To unravel the synthesis of highly fucosylated N-glycans by S. mansoni, we examined the ability of ten selected SmFucTs to modify N-glycans upon transient expression in Nicotiana benthamiana plants. All enzymes were localized in the plant Golgi apparatus, which allowed us to identify the SmFucTs involved in core fucosylation and the synthesis of complex antennary glycan motifs. This knowledge provides a starting point for investigations into the role of specific fucosylated glycan motifs of schistosomes in parasite-host interactions. The functionally characterized SmFucTs can also be applied to synthesize complex N-glycan structures on recombinant proteins to study their contribution to immunomodulation. Furthermore, this plant expression system will fuel the development of helminth glycoproteins for pharmaceutical applications or novel anti-helminth vaccines.
وصف الملف: application/pdf
العلاقة: https://radar.brookes.ac.uk/radar/items/79f2da7d-3786-4f57-856b-3fb250fab8f7/1Test/; https://radar.brookes.ac.uk/radar/file/79f2da7d-3786-4f57-856b-3fb250fab8f7/1/s41598-020-74485-z.pdfTest
