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Biomolecules Feb 2024Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to... (Review)
Review
Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes-namely, protein assemblies-under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation's influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease.
Topics: Glycosylation; Protein Processing, Post-Translational; Polysaccharides; Protein Conformation; Prions
PubMed: 38540703
DOI: 10.3390/biom14030282 -
International Journal of Molecular... Nov 2023Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental... (Review)
Review
Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions.
Topics: Pregnancy; Female; Humans; Placenta; Glycosylation; Immunoglobulin G; Trophoblasts; Immunomodulation; Maternal-Fetal Exchange
PubMed: 38069094
DOI: 10.3390/ijms242316772 -
Nature Communications Jan 2024The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing...
The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease.
Topics: Humans; COVID-19; Glycosylation; SARS-CoV-2; Glycosyltransferases; Complement System Proteins; Immunoglobulin M
PubMed: 38195739
DOI: 10.1038/s41467-023-44211-0 -
Taiwanese Journal of Obstetrics &... Sep 2023Sialic acids (SA) are a kind of nine-carbon backbone sugars, serving as important molecules in cell-to-cell or cell-to-extra-cellular matrix interaction mediated by... (Review)
Review
Sialic acids (SA) are a kind of nine-carbon backbone sugars, serving as important molecules in cell-to-cell or cell-to-extra-cellular matrix interaction mediated by either O-linked glycosylation or N-linked glycosylation to attach the terminal end of glycans, glycoproteins, and glycolipids. All processes need a balance between sialylation by sialyltransferase (STs) and desialylation by sialidases (also known as neuraminidases, NEU). Although there is much in uncertainty whether the sialyation plays in cancer development and progression, at least four mechanisms are proposed, including surveillance of immune system, modification of cellular apoptosis and cell death, alteration of cellular surface of cancer cells and tumor associated microenvironment responsible carcinogenesis, growth and metastases. The current review focuses on the role of glycosylation in gynecologic organ-related cancers, such as ovarian cancer, cervical and endometrial cancer. Evidence shows that sialylation involving in the alternation of surface components of cells (tumor and cells in the microenvironment of host) plays an important role for carcinogenesis (escape from immunosurveillance) and dissemination (metastasis) (sloughing from the original site of cancer, migration into the circulation system, extravasation from the circulatory system to the distant site and finally deposition and establishment on the new growth lesion to complete the metastatic process). Additionally, modification of glycosylation can enhance or alleviate the aggressive characteristics of the cancer behaviors. All suggest that more understandings of glycosylation on cancers may provide a new therapeutic field to assist the cancer treatment in the near future.
Topics: Female; Humans; Genital Neoplasms, Female; Ovarian Neoplasms; Endometrial Neoplasms; Carcinogenesis; Glycosylation; Tumor Microenvironment
PubMed: 37678990
DOI: 10.1016/j.tjog.2023.07.034 -
Journal of Immunology (Baltimore, Md. :... Dec 2023Complement activation via the classical pathway is initiated when oligomeric Igs on target surfaces are recognized by C1 of the complement cascade. The strength of this...
Complement activation via the classical pathway is initiated when oligomeric Igs on target surfaces are recognized by C1 of the complement cascade. The strength of this interaction and activation of the complement system are influenced by structural variation of the Ab, including Ab isotype, subclass, and glycosylation profile. Polymorphic variants of IgG have also been described to influence Fc-dependent effector functions. Therefore, we assessed complement binding, deposition, and complement-dependent cytotoxicity (CDC) of 27 known IgG allotypes with anti-trinitrophenyl specificity. Differences between allotypes within subclasses were minor for IgG1, IgG3, and IgG4 allotypes, and more substantial for IgG2. Allelic variant IGHG2*06, containing a unique serine at position 378 in the CH3 domain, showed less efficient complement activation and CDC compared with other IgG2 polymorphisms. We also observed variable cell lysis between IgG1 and IgG3, with IgG3 being superior in lysis of human RBCs and Ramos cells, and IgG1 being superior in lysis of Raji and Wien133 cells, demonstrating that a long-standing conundrum in the literature depends on cellular context. Furthermore, we compared IgG1 and IgG3 under different circumstances, showing that Ag density and Ab hinge length, but not complement regulators, define the context dependency of Ab-mediated CDC activity. Our results point toward a variation in the capacity of IgG subclasses to activate complement due to single amino acid changes and hinge length differences of allotypes to activate complement, which might give new insights on susceptibility to infectious, alloimmune, or autoimmune diseases and aid the design of Ab-based therapeutics.
Topics: Humans; Immunoglobulin G; Complement Activation; Glycosylation
PubMed: 37843500
DOI: 10.4049/jimmunol.2300307 -
Proceedings of the National Academy of... Sep 2023Neutrophils store microbicidal glycoproteins in cytosolic granules to fight intruding pathogens, but their granule distribution and formation mechanism(s) during...
Neutrophils store microbicidal glycoproteins in cytosolic granules to fight intruding pathogens, but their granule distribution and formation mechanism(s) during granulopoiesis remain unmapped. Herein, we comprehensively profile the neutrophil -glycoproteome with spatiotemporal resolution by analyzing four key types of intracellular organelles isolated from blood-derived neutrophils and during their maturation from bone marrow-derived progenitors using a glycomics-guided glycoproteomics approach. Interestingly, the organelles of resting neutrophils exhibited distinctive glycophenotypes including, most strikingly, highly truncated -glycans low in α2,6-sialylation and Lewis fucosylation decorating a diverse set of microbicidal proteins (e.g., myeloperoxidase, azurocidin, neutrophil elastase) in the azurophilic granules. Excitingly, proteomics and transcriptomics data from discrete myeloid progenitor stages revealed that profound glycoproteome remodeling underpins the promyelocytic-to-metamyelocyte transition and that the glycophenotypic differences are driven primarily by dynamic changes in protein expression and less by changes within the glycosylation machinery. Notable exceptions were the oligosaccharyltransferase subunits responsible for initiation of -glycoprotein biosynthesis that were strongly expressed in early myeloid progenitors correlating with relatively high levels of glycosylation of the microbicidal proteins in the azurophilic granules. Our study provides spatiotemporal insights into the complex neutrophil -glycoproteome featuring intriguing organelle-specific -glycosylation patterns formed by dynamic glycoproteome remodeling during the early maturation stages of the myeloid progenitors.
Topics: Glycosylation; Neutrophils; Proteome; Cognition; Cytoplasmic Granules
PubMed: 37639587
DOI: 10.1073/pnas.2303867120 -
Frontiers in Immunology 2023Immunoglobulin G (IgG) antibodies are a critical component of the adaptive immune system, binding to and neutralizing pathogens and other foreign substances. Recent... (Review)
Review
Immunoglobulin G (IgG) antibodies are a critical component of the adaptive immune system, binding to and neutralizing pathogens and other foreign substances. Recent advances in molecular antibody biology and structural protein engineering enabled the modification of IgG antibodies to enhance their therapeutic potential. This review summarizes recent progress in both natural and engineered structural modifications of IgG antibodies, including allotypic variation, glycosylation, Fc engineering, and Fc gamma receptor binding optimization. We discuss the functional consequences of these modifications to highlight their potential for therapeutical applications.
Topics: Immunoglobulin G; Receptors, IgG; Gamma Rays; Glycosylation; Molecular Biology
PubMed: 38259472
DOI: 10.3389/fimmu.2023.1304365 -
Nature Communications Nov 2023The precise modification or functionalization of the protein C-terminus is essential but full of challenges. Herein, a chemical approach to modify the C-terminus is...
The precise modification or functionalization of the protein C-terminus is essential but full of challenges. Herein, a chemical approach to modify the C-terminus is developed by fusing a cysteine protease domain on the C-terminus of the protein of interest, which could achieve the non-enzymatic C-terminal functionalization by InsP-triggered cysteine protease domain self-cleavage. This method demonstrates a highly efficient way to achieve protein C-terminal functionalization and is compatible with a wide range of amine-containing molecules and proteins. Additionally, a reversible C-terminal de-functionalization is found by incubating the C-terminal modified proteins with cysteine protease domain and InsP, providing a tool for protein functionalization and de-functionalization. Last, various applications of protein C-terminal functionalization are provided in this work, as demonstrated by the site-specific assembly of nanobody drug conjugates, the construction of a bifunctional antibody, the C-terminal fluorescent labeling, and the C-terminal transpeptidation and glycosylation.
Topics: Protein C; Proteins; Glycosylation; Cysteine Proteases; Cysteine
PubMed: 37935692
DOI: 10.1038/s41467-023-42977-x -
Molecules (Basel, Switzerland) Jul 2023Controlling the stereoselectivity of 1,2- glycosylation is one of the most challenging tasks in the chemical synthesis of glycans. There are various 1,2- glycosides in... (Review)
Review
Controlling the stereoselectivity of 1,2- glycosylation is one of the most challenging tasks in the chemical synthesis of glycans. There are various 1,2- glycosides in nature, such as α-glucoside and β-mannoside in glycoproteins, glycolipids, proteoglycans, microbial polysaccharides, and bioactive natural products. In the structure of polysaccharides such as α-glucan, 1,2- α-glucosides were found to be the major linkage between the glucopyranosides. Various regioisomeric linkages, 1→3, 1→4, and 1→6 for the backbone structure, and 1→2/3/4/6 for branching in the polysaccharide as well as in the oligosaccharides were identified. To achieve highly stereoselective 1,2- glycosylation, including α-glucosylation, a number of strategies using inter- and intra-molecular methodologies have been explored. Recently, Zn salt-mediated glycosylation has been developed and applied to the synthesis of various 1,2- linkages, such as α-glucoside and β-mannoside, via the 1,2- glycosylation pathway and β-galactoside 1,4/6- induction. Furthermore, the synthesis of various structures of α-glucans has been achieved using the recent progressive stereoselective 1,2- glycosylation reactions. In this review, recent advances in stereoselective 1,2- glycosylation, particularly focused on α-glucosylation, and their applications in the construction of linear and branched α-glucans are summarized.
Topics: Glycosylation; Polysaccharides; Glucans; Glucosides; Mannosides; Stereoisomerism
PubMed: 37570614
DOI: 10.3390/molecules28155644 -
International Journal of Molecular... Mar 2024Glycosylation plays a crucial role in the maintenance of homeostasis in the body and at the onset of diseases such as inflammation, neurodegeneration, infection,... (Review)
Review
Glycosylation plays a crucial role in the maintenance of homeostasis in the body and at the onset of diseases such as inflammation, neurodegeneration, infection, diabetes, and cancer. It is also involved in bone metabolism. - and -glycans have been shown to regulate osteoblast and osteoclast differentiation. We recently demonstrated that ganglio-series and globo-series glycosphingolipids were essential for regulating the proliferation and differentiation of osteoblasts and osteoclasts in glycosyltransferase-knockout mice. Herein, we reviewed the importance of the regulation of bone metabolism by glycoconjugates, such as glycolipids and glycoproteins, including our recent results.
Topics: Animals; Mice; Glycosylation; Homeostasis; Glycosyltransferases; Glycolipids; Inflammation; Mice, Knockout
PubMed: 38612379
DOI: 10.3390/ijms25073568