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Carbohydrates are ubiquitous modifications of eukaryotic cell surface proteins and lipids. Glycans. Localization of glycoconjugates in intracellular and extracellular compartments . Glycans. Functions. Extrinsic functions resulting from glycan-lectin interactions. Intrinsic functions
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Carbohydrates are ubiquitous modifications of eukaryotic cell surface proteins and lipids.
Glycans Localization of glycoconjugates in intracellular and extracellular compartments
Glycans Functions Extrinsic functions resulting from glycan-lectin interactions Intrinsic functions performed by glycans Directing trafficking of glycoconjugates Intracellular Extracellular Mediating and modulating cell adhesion Cell-cell interactions Cell-matrix interactions Mediating and modulating signaling Intracellular Extracellular Providing structural components Cell walls Extracellular matrix Modifying protein properties Solubility Stability
Glycans: Structures Three major classes of glycoconjugates Attached to proteins * through a nitrogen atom of asparagine (N-linked) ** through an oxygen atom of serine or threonine (O-linked) *** Attached to lipids
HC=O 1 HC=O 1 HCOH 2 2 HCOH HOCH 3 Epimerization at C4 HOCH 3 HCOH 4 HOCH 4 HCOH 5 5 HCOH 6 CH2OH 6 CH2OH Glycans: Structures Glycans are composed of monosaccharides with related chemical structures Glucose Galactose Hexoses are the most common constituents of glycans
Glycans: Structures Two ways to form a pyranose (6-member) ring from glucose
Glycans: Structures Substitution of the 2-hydroxyl group of glucose or galactose with acetamido group yields N-acetylhexosamines
Glycans: Structures Common derivatives of the hexoses
Glycans: Structures Structure of N-acetylneuraminic acid, the most common form of sialic acid
Glycans: Structures Glycosidic linkages between monosaccharides exist in multiple configurations
Glycans: Structures A typical N-linked glycan Chemical structure Word structure Symbol structure
Uridine diphosphate (UDP) Glycans: Structures Formation of glycosidic linkages require energy and catalyzed by specific enzymes, glycosyltransferases Glycosyltransferase reaction UDP-galactose, an example of a nucleotide sugar donor
Glycans: Structures Understanding structure-function relationship for glycans can be more difficult than for other classes of biopolymers * The functions of polypeptide and glycan portions of glycoproteins are potentially independent
Glycans: Structures Understanding structure-function relationship for glycans can be more difficult than for other classes of biopolymers ** Monosaccharides generate more linkage variation than amino acids or nucleotides Example: structure# of variations 3 nucleotide bases 6 3 amino acids 6 3 hexoses 1,056 - 27,648
Glycans: Structures Glycan structures are encoded indirectly in the genome
Glycans Functions Extrinsic functions resulting from glycan-lectin interactions Intrinsic functions performed by glycans Directing trafficking of glycoconjugates Intracellular Extracellular Mediating and modulating cell adhesion Cell-cell interactions Cell-matrix interactions Mediating and modulating signaling Intracellular Extracellular Providing structural components Cell walls Extracellular matrix Modifying protein properties Solubility Stability
Core protein Linkage region Xylose Galactose GlcNAc GlcA I. Heparan sulfate proteoglycans Disaccharide unit Sulfate IdoA Large O-linked chains of as many as a hundred residues
Abnormalities in heparan sulfate biosynthesis is implicated in the human multiple exostoses syndrome
II. Notch signaling Notch proteins mediate a wide variety of cell fate decisions during development: in Drosophila: - Organogenesis and pattern formation - Neurogenesis - Myogenesis - Oogenesis - etc. Malfunctioning of Notch signaling causes: - Human T-cell lymphoblastic leukaemia (TAN-1/Notch1) - Human stroke and dementia (CADASIL, Notch3) - Spondylocostal dysostosis (Dll3) - Alagille syndrome (Jagged1) - Murine breast cancer (int-3/Notch4) in Vertebrates (4 Notch genes, 5 ligands): - Somitogenesis - Neurogenesis - T-cell development - etc.
GlcNAc + Fringe O-fucose Serrate Notch Delta
Glycans Functions Extrinsic functions resulting from glycan-lectin interactions Intrinsic functions performed by glycans Directing trafficking of glycoconjugates Intracellular Extracellular Mediating and modulating cell adhesion Cell-cell interactions Cell-matrix interactions Mediating and modulating signaling Intracellular Extracellular Providing structural components Cell walls Extracellular matrix Modifying protein properties Solubility Stability
Normal muscle Muscular dystrophy Basal Lamina Neurexin Neurexin Laminin Laminin Agrin Agrin O-mannosyl glycans Extracellular a a Dystroglycan Dystroglycan b b Membrane Dystrophin Dystrophin Intracellular Actin-filament Actin-filament
Functions: III. O-mannosylation in muscular dystrophies Compromised O-mannosylation of dystroglycan causes severe muscle and brain abnormalities Muscle biopsy: Dystrophic changes Example: Muscle-eye-brain disease: congenital muscular dystrophy, severe congenital myopia, hydrocephalus, mental retardation Cranial MRI: Cerebellar hypoplasia Neuronal migration disorder Yoshida et al., Dev. Cell 2001
Muscular dystrophies associated with mutations in glycosyltransferase genes.
Galactose GalNAc Fucose Glycans: Functions IV. ABO blood groups (1900s, Landsteiner et al.) Alleles: Encode glycosyltransferases: IO IA IB Inactive GalNAc-transferase Gal-transferase The glycan antigens are expressed on the surface of red blood cells and determine the compatibility in blood transfusions
Structure Functions Glycans Directing trafficking of glycoconjugates Intracellular Extracellular Mediating and modulating cell adhesion Cell-cell interactions Cell-matrix interactions Mediating and modulating signaling Intracellular Extracellular Providing structural components Cell walls Extracellular matrix Modifying protein properties Solubility Stability