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      “Stuck on sugars – how carbohydrates regulate cell adhesion, recognition, and signaling”

      Glycoconjugate Journal

      Springer Science and Business Media LLC

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          Abstract

          We have explored the fundamental biological processes by which complex carbohydrates expressed on cellular glycoproteins and glycolipids and in secretions of cells promote cell adhesion and signaling. We have also explored processes by which animal pathogens, such as viruses, bacteria, and parasites adhere to glycans of animal cells and initiate disease. Glycans important in cell signaling and adhesion, such as key O-glycans, are essential for proper animal development and cellular differentiation, but they are also involved in many pathogenic processes, including inflammation, tumorigenesis and metastasis, and microbial and parasitic pathogenesis. The overall hypothesis guiding these studies is that glycoconjugates are recognized and bound by a growing class of proteins called glycan-binding proteins (GBPs or lectins) expressed by all types of cells. There is an incredible variety and diversity of GBPs in animal cells involved in binding N- and O-glycans, glycosphingolipids, and proteoglycan/glycosaminoglycans. We have specifically studied such molecular determinants recognized by selectins, galectins, and many other C-type lectins, involved in leukocyte recruitment to sites of inflammation in human tissues, lymphocyte trafficking, adhesion of human viruses to human cells, structure and immunogenicity of glycoproteins on the surfaces of human parasites. We have also explored the molecular basis of glycoconjugate biosynthesis by exploring the enzymes and molecular chaperones required for correct protein glycosylation. From these studies opportunities for translational biology have arisen, involving production of function-blocking antibodies, anti-glycan specific antibodies, and synthetic glycoconjugates, e.g. glycosulfopeptides, that specifically are recognized by GBPs. This invited short review is based in part on my presentation for the IGO Award 2019 given by the International Glycoconjugate Organization in Milan.

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          Most cited references 164

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          Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds.

           R G Spiro (2002)
          Formation of the sugar-amino acid linkage is a crucial event in the biosynthesis of the carbohydrate units of glycoproteins. It sets into motion a complex series of posttranslational enzymatic steps that lead to the formation of a host of protein-bound oligosaccharides with diverse biological functions. These reactions occur throughout the entire phylogenetic spectrum, ranging from archaea and eubacteria to eukaryotes. It is the aim of this review to describe the glycopeptide linkages that have been found to date and specify their presence on well-characterized glycoproteins. A survey is also made of the enzymes involved in the formation of the various glycopeptide bonds as well as the site of their intracellular action and their affinity for particular peptide domains is evaluated. This examination indicates that 13 different monosaccharides and 8 amino acids are involved in glycoprotein linkages leading to a total of at least 41 bonds, if the anomeric configurations, the phosphoglycosyl linkages, as well as the GPI (glycophosphatidylinositol) phosphoethanolamine bridge are also considered. These bonds represent the products of N- and O-glycosylation, C-mannosylation, phosphoglycation, and glypiation. Currently at least 16 enzymes involved in their formation have been identified and in many cases cloned. Their intracellular site of action varies and includes the endoplasmic reticulum, Golgi apparatus, cytosol, and nucleus. With the exception of the Asn-linked carbohydrate and the GPI anchor, which are transferred to the polypeptide en bloc, the sugar-amino acid linkages are formed by the enzymatic transfer of an activated monosaccharide directly to the protein. This review also deals briefly with glycosidases, which are involved in physiologically important cleavages of glycopeptide bonds in higher organisms, and with a number of human disease states in which defects in enzymatic transfer of saccharides to protein have been implicated.
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            Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family.

             Eric Bennett (corresponding) ,  Ulla Mandel,  Henrik Clausen (2012)
            Glycosylation of proteins is an essential process in all eukaryotes and a great diversity in types of protein glycosylation exists in animals, plants and microorganisms. Mucin-type O-glycosylation, consisting of glycans attached via O-linked N-acetylgalactosamine (GalNAc) to serine and threonine residues, is one of the most abundant forms of protein glycosylation in animals. Although most protein glycosylation is controlled by one or two genes encoding the enzymes responsible for the initiation of glycosylation, i.e. the step where the first glycan is attached to the relevant amino acid residue in the protein, mucin-type O-glycosylation is controlled by a large family of up to 20 homologous genes encoding UDP-GalNAc:polypeptide GalNAc-transferases (GalNAc-Ts) (EC 2.4.1.41). Therefore, mucin-type O-glycosylation has the greatest potential for differential regulation in cells and tissues. The GalNAc-T family is the largest glycosyltransferase enzyme family covering a single known glycosidic linkage and it is highly conserved throughout animal evolution, although absent in bacteria, yeast and plants. Emerging studies have shown that the large number of genes (GALNTs) in the GalNAc-T family do not provide full functional redundancy and single GalNAc-T genes have been shown to be important in both animals and human. Here, we present an overview of the GalNAc-T gene family in animals and propose a classification of the genes into subfamilies, which appear to be conserved in evolution structurally as well as functionally.
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              Apoptosis of T cells mediated by galectin-1.

              Galectin-1, a member of the family of beta-galactoside binding proteins, has growth regulatory and immunomodulatory activities. We report here that galectin-1, expressed by stromal cells in human thymus and lymph nodes, is present at sites of cell death by apoptosis during normal T-cell development and maturation. Galectin-1 induced apoptosis of activated human T cells and human T leukaemia cell lines. Resting T cells also bound galectin-1, but did not undergo apoptosis. Human endothelial cells that expressed galectin-1 induced apoptosis of bound T cells. Galectin-1-induced apoptosis required expression of CD45, and was decreased when N-glycan elongation was blocked by treatment of the cells by swainsonine, whereas inhibition of O-glycan elongation potentiated the apoptotic effect of galectin-1. Induction of apoptosis by an endogenous mammalian lectin represents a new mechanism for regulating the immune response.
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                Author and article information

                Journal
                Glycoconjugate Journal
                Glycoconj J
                Springer Science and Business Media LLC
                0282-0080
                1573-4986
                August 2019
                July 2 2019
                August 2019
                : 36
                : 4
                : 241-257
                Article
                10.1007/s10719-019-09876-0
                6657361
                31267247
                8f98bf1b-fd1a-437c-944d-be5534bff636
                © 2019

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