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Role of Membrane Glycoproteins in Mediating Trophic Responses

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Role of Membrane Glycoproteins in Mediating Trophic Responses Gut: first published as 10.1136/gut.28.Suppl.71 on 1 January 1987. Downloaded from Gut, 1987, 28, Sl, 71-77 Role of membrane glycoproteins in mediating trophic responses R TAUBER, W REUTTER, AND W GEROK Medizinische Klinik der Universitdt Freiburg, Freiburg i Br, Federal Republic of Germany, and Institut far Molekularbiologie und Biochemie der Freien Universitdt, Berlin, FRG SUMMARY During growth and differentiation the plasma membrane has a key role not only in the reception and transmission of extracellular signals such as hormones and growth factors, but also in communicating cellular response to the cellular microenvironment. Cellular response to trophic stimuli includes alterations of cell shape and cell surface antigenicity,l of cell-cell recognition and cellular adhesion,2 of cell matrix binding3 and the adaptation of cell surface receptors.4 The plasma membrane is therefore regarded as a 'central agency' for the integration of a single cell into the complex system of a tissue or of an organism. The numerous functions of the plasma membrane are mainly mediated by membrane integrated glycoproteins or glycolipids both sharing the common feature of covalently bound oligosaccharide side chains. Specific alterations of oligosaccharide structure and metabolism associated with growth, differentiation and various pathologic conditions suggest a specific role for the oligosaccharide moieties in the regulation of cell surface functions (Table 1). This review intends to focus on the role of plasma membrane glycoproteins describing briefly principles of glycoprotein structure and function, and characteristics of their biosynthesis and degradation. http://gut.bmj.com/ Structure of plasma membrane glycoproteins have a third cytoplasmic domain.'5 The membrane anchor sequence of transmembrane glycoproteins is The polypeptide backbone of plasma membrane flanked by basic sequences which may interact with glycoproteins is constituted by at least two domains, the head groups of negatively charged phospho- a sequence rich in hydrophobic amino acids which lipids.'5 on September 24, 2021 by guest. Protected copyright. anchors them to the lipid bilayer, and a hydrophilic Oligosaccharide side chains of glycoproteins are domain at the extracellular membrane surface. Several exclusively bound to the extracellular polypeptide glycoproteins such as the insulin receptor, the EGF domain extending into the microenvironment of the receptor or the LDL receptor span the membrane and cell. Structural analysis by use of 360 and 500 MHz 'H-NMR or sequential exoglycosidase digestion has Table 1 Alterations of oligosaccharide structures of shown that oligosaccharides of glycoproteins fall into plasma membrane glycoproteins two classes according to the type oftheir carbohydrate polypeptide linkage (Fig. 1,16) (a) 0-glycosidic linkage Selected references from N-acetyl-D-galactosamine to hydroxyamino Differentiation 5 acids (serine, threonine), (b) N-glycosidic linkage Growth 6 7 from N-acetyl-D-glucosamine to the amide nitrogen Mutation 8 of asparagine. Hypervitaminosis (retinol) 9 10 Asparagine linked oligosaccharides have Malignancy 1112 a Cystic fibrosis 13 common core structure consisting of a branched Psoriasis 14 pentasaccharide Manal-3 (Manal-6) Man/Il- 4GlcNAc,/1-4 GIcNAc-Asn. To the peripheral man- Address for correspondence: Prof R Tauber, Institut fur Klinische Chemie und nose residues different types of side chains are linked Biochemie, Universitatsklinikum Charlottenburg, Spandauer Damm 130, giving rise to three D-1000 Berlin 19, FRG structural subgroups. High This study is dedicated to Prof P Scholmerich on the occasion of his mannose or oligomannosyl oligosaccharides are sub- 70th birthday stituted with additional mannose residues, whereas 71 Gut: first published as 10.1136/gut.28.Suppl.71 on 1 January 1987. Downloaded from 72 Tauber, Reutter, and Gerok r-- -- - -- -- -- --- --- .-1-- iL 2Man c Man1 _ 6 36Man 131 - 4G1cNAc o13 4G1cNAc--e Asn Man a1 t 2Man cxl NeuAcci2 6Galf3l 4G1cNAcJ31 - 2Mancxl _ la I~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ NeuAccx2 6Ga1l31 _ 4G1cNAc31 2Mana1c I 1 Man cil 6 I 6Man (x1 Mancril 3 NeuAcai2 _ 6Ga1/31 _ 4GlcNacf3l r 2Mancal Gal (31 3G1cNAc(31 --3Gal(3 3Ga1NAc _ ser(thr) IV 6 Ga1,31 4G1cNAcI3 Fig. 1 Representative structures of N-linked and 0-linked oligosaccharide chains. I: High mannose type, II: complex type, III: hybrid type of N-linked oligosaccharides; IV: 0-linked structure. Fuc, L-fucose; Gal, D-galactose; GalNAc, N-acetyl-D-galactosamine; GlcNAc, N-acetyl-D-glucosamine; Man, D-mannose; NeuAc, N-acetylneuraminic acid. http://gut.bmj.com/ complex type oligosaccharides contain two, three, core. In A, B, and H (0) blood group determinants four or five outer branches consisting of one lactos- galactose, L-fucose and N-acetyl-D-galactosamine amine sequence Gal/I1-4GlcNAc or repeating lactos- residues are bound to this disaccharide in different amine units. To the galactose or N-acetyl-D-glucos- positions. amine residues of the lactosamine sequence L-fucose The structural diversity of oligosaccharides is or N-acetylneuraminic acid may be linked as terminal extended by their spatial conformation (for review substituents. Additionally, L-fucose may be linked to see. 18) Biantennary oligosaccharides -for example, on September 24, 2021 by guest. Protected copyright. the C-6 position of the innermost N-acetyl-D- may form three dimensional structures shaped like a glucosamine residue. Polysialosyl sequences with up T or Y thus exposing also sugar sequences in an inner to 12 sialic acid residues have been found in rat position. Formation of three dimensional structures brain.'7 Thirdly, hybrid oligosaccharides share the involves mutual interactions with the protein moiety feature of both high mannose and complex type and is therefore subject also to alterations of the oligosaccharides containing both oligomannosyl and amino acid sequence. Moreover, removal of terminal lactosamine side chains. neuraminic acid residues forming non-covalent bonds By varying the sugar composition of the outer with basic amino acids of the polypeptide, may chains, the degree of branching and the type of the modify the conformation of the oligosaccharide. glycosidic linkages a tremendously high number of Because glycosidic linkages are partly able to rotate, different oligosaccharides structures may be gener- oligosaccharides of glycoproteins must be regarded as ated. Nevertheless, except for a certain microhetero- flexible structures. geneity, the individual glycosylation sites of a glyco- protein have a high selectivity for a particular Functions of plasma membrane glycoproteins oligosaccharide structure indicating that oligo- saccharide biosynthesis must be specifically regulated. Because of their structural diversity and modifiability Unlike N-linked oligosaccharides 0-glycosyl units 0- and N-linked oligosaccharides of plasma mem- have no common partial structure varying from brane glycoproteins serve as carriers of biological disaccharides to complex branched oligosaccharides information either modulating the properties of often attached to a Gal/31-3GalNAc disaccharide functional glycoproteins or serving as specific signals Gut: first published as 10.1136/gut.28.Suppl.71 on 1 January 1987. Downloaded from Role ofmembrane glycoproteins in mediating trophic response 73 Table 2 Functions of the oligosaccharide moiety of portant signals - for example, in interce!lular ad- glycoproteins hesion.23 Treatment of BHK cells with neuraminidase exposing terminal f6-galactosyl residues has been Physicochemical modulation: shown to increase cellular aggregation, whereas - tertiary conformation - solubility additional removal of the galactose residue decreases - viscosity the aggregation potential of the cells." Similarly, a - electrical charge switch in glycoprotein biosynthesis from complex - stabilisation against proteolysis type oligosaccharides to high mannose structures Determinants of biological recognition: - cell-cell recognition and adhesion results in lower cell-cell aggregation." - cell-matrix adhesion As first suggested by Roseman,32 surface located - sorting signals for intracellular transport and compart- oligosaccharides of plasma membrane glycoproteins mentation or glycolipids are thought to mediate cellular recog- - signals for receptor-mediated endocytosis (clearance of serum glycoproteins, non-immune phagocytosis) nition and adhesion by binding to complementary - cell surface antigens, differentiation markers binding sites exposed on the surface of adjacent cells. - binding sites for viruses and bacteria (hostparasite relation- This conception originally proposed for cell surface ship) glycosyltransferases was restored to prominence by the discovery by Ashwell of cell surface receptor in numerous recognition systems (Table 2, for proteins with binding specificity for mono- and review)."9"20 oligosaccharides.33 Numerous mammalian lectins with different carbohydrate specificity have been PLASMA MEMBRANE GLYCOPROTEINS IN characterised on the surface of various cell types (for INTERCELLULAR RECOGNITION AND ADHESION review see.34-36) Figure 2 schematically shows how The ability of cells to recognise and to bind to each binding of a complex N-linked oligosaccharide to a other specifically is a prerequisite for the development galactose specific lectin is controlled by the terminal of multicellular organisms. Intercellular communi- sugar sequence. Binding to the lectin is initiated by the cation moreover plays pivotal roles in fertilisation,
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