The extracellular space also has its own class of glycoconjugates. The cell surface and connective matrix of animal tissues are populated by large proteoglycan molecules which have covalently attached glycosaminoglycan chains (GAGs) that may be either
N-linked or O-linked to the core protein. GAGs are linear polysaccharides that consist of repeating disaccharide units of hexuronic acid linked to a hexosamine. These large polysaccharides are acidic and/or polyanionic (negatively charged due to numerous sulfate groups). GAG biosynthesis occurs without a template and is largely controlled by enzyme and substrate availabilities, giving rise to a heterogeneous mixture of glycoforms (1). The diverse structural properties of GAGs are important for molecular binding and for tissue morphogenesis (2-4) (Fig. 1). The majority of GAGs are first attached to the core protein and polymerized in the Golgi apparatus, where they are subsequently sulfated following various patterns that greatly affect the biological properties of the molecule. One exception is hyaluronan, which is a non-sulfated free polysaccharide, synthesized at the plasma membrane level (5).
Figure 1: Scheme showing some proteoglycans and other GAGs of the extracellular space. An example of membrane-bound proteoglycan is syndecan, which is commonly present in fibroblasts. This molecule has several heparan sulfate chains that participate in growth factor binding and tissue differentiation. Aggrecan and biglycan are common proteoglycans of the interstitial space. The chondroitin sulfate chains allow aggrecan to form hydrated gels, in complexes with the free polysaccharide hyaluronan. These negatively charged aggregates, in turn, interact with collagen (insert) providing the scaffold for tissues with highly compressive and tensile properties, such as cartilage.
Glycolipids comprise another major class of glycans. These molecules are abundant components of the cellular membrane and consist of a lipid moiety attached to monosaccharide or polysaccharide chains that extend into the extracellular space. There are several classes of glycolipids, including glyceroglycolipids, lipopolysaccharides, glycosphingolipids, and glycosylphosphatidylinositols (6). These molecules have varied functions such as eliciting host immune responses to bacterial infections, modulating cell-cell communication and ensuring proper myelination of axons (7, 8).
One interesting class of glycolipids is the glycosylphosphatidylinositol (GPI) anchor. GPIs are essential molecules that are attached to the carboxy termini of certain proteins and serve to anchor them to the surface of eukaryotic cells. GPI anchored proteins are involved in a diverse array of cellular processes including cell adhesion and signal transduction. Proteins that receive a GPI possess a C-terminal GPI attachment signal peptide that mediates enzymatic addition of a GPI precursor lipid to the protein in the ER. The GPI anchored protein then transits the compartments of the ER and Golgi to the cell surface where it is displayed on the exterior face of the plasma membrane. During this journey, specific enzymes add and subtract components side-branched to the GPI glycan, and remodel the fatty acids of the GPI’s lipid moiety. GPI anchored proteins also typically possess
N- and/or O-linked glycans (Fig. 2). GPI anchors seem to have implications in the trafficking and surface localization of a given protein, for instance there seems to be a higher abundance of GPI-anchored proteins in lipid rafts (9).
Figure 2: Schematic representation of the main events in the synthesis of GPI-anchored proteins. Proteins (often glycoproteins) acquire a GPI anchor in the ER, a signal sequence is cleaved (at a consensus omega residue) and the GPI anchor is attached via a terminal ethanolamine phosphate to the C-termini of the acceptor protein. The glycolipid moiety can be later modified in the Golgi. The mature glycoprotein is finally localized to the plasma membrane. References
Proteoglycans and Sulfated Glycosaminoglycans. Jeffrey D Esko, Koji Kimata, and Ulf Lindahl. In Essentials of Glycobiology. 2nd edition. Varki A, Cummings RD, Esko JD, et al., editors. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. PMID:
20301236 Heinegård D. (2009) Int J Exp Pathol. 90(6):575-86. PMID:
19958398 Sarrazin S, et al. (2011) Cold Spring Harb Perspect Biol. 3(7). pii: a004952. PMID:
21690215 Haylock-Jacobs S, et al. (2011) Autoimmun Rev. 10(12):766-72. PMID:
21664302 Maccioni HJ. (2007) J Neurochem.103 Suppl 1:81-90. PMID:
17986143 Bastow ER, et al. (2008) Cell Mol Life Sci. 65(3):395-413. PMID:
17965830 Zajonc DM, Kronenberg M. (2009) Immunol Rev. 230(1):188-200. PMID:
19594637 Stoffel W, Bosio A. (1997) Curr Opin Neurobiol. 7(5):654-61. PMID:
9384539 Paulick MG, Bertozzi CR. (2008) Biochemistry. 47(27):6991-7000. PMID: