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Carbohydrates are ubiquitous modifications of eukaryotic cell surface proteins and lipids.

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Presentation on theme: "Carbohydrates are ubiquitous modifications of eukaryotic cell surface proteins and lipids."— Presentation transcript:

1 Carbohydrates are ubiquitous modifications of eukaryotic cell surface proteins and lipids.

2 Glycans Localization of glycoconjugates in intracellular and extracellular compartments

3 Providing structural components Cell walls Extracellular matrix Modifying protein properties Solubility Stability Directing trafficking of glycoconjugates Intracellular Extracellular Mediating and modulating cell adhesion Cell-cell interactions Cell-matrix interactions Mediating and modulating signaling Intracellular Extracellular Functions Extrinsic functions resulting from glycan-lectin interactions Intrinsic functions performed by glycans Glycans

4 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 Glycans: Structures

5 Glycans are composed of monosaccharides with related chemical structures HC=O HCOH HOCH CH 2 OH HOCH HC=O HCOH HOCH CH 2 OH Epimerization at C4 GlucoseGalactose Hexoses are the most common constituents of glycans Glycans: Structures

6 Two ways to form a pyranose (6-member) ring from glucose Glycans: Structures

7 Substitution of the 2-hydroxyl group of glucose or galactose with acetamido group yields N-acetylhexosamines Glycans: Structures

8 Common derivatives of the hexoses Glycans: Structures

9 Structure of N-acetylneuraminic acid, the most common form of sialic acid Glycans: Structures

10 Glycosidic linkages between monosaccharides exist in multiple configurations Glycans: Structures

11 A typical N-linked glycan Chemical structure Word structure Symbol structure Glycans: Structures

12 Formation of glycosidic linkages require energy and catalyzed by specific enzymes, glycosyltransferases Glycosyltransferase reaction UDP-galactose, an example of a nucleotide sugar donor Uridine diphosphate (UDP) Glycans: Structures

13 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

14 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, ,648 Glycans: Structures

15 Glycan structures are encoded indirectly in the genome

16 Providing structural components Cell walls Extracellular matrix Modifying protein properties Solubility Stability Directing trafficking of glycoconjugates Intracellular Extracellular Mediating and modulating cell adhesion Cell-cell interactions Cell-matrix interactions Mediating and modulating signaling Intracellular Extracellular Functions Extrinsic functions resulting from glycan-lectin interactions Intrinsic functions performed by glycans Glycans

17 I. Heparan sulfate proteoglycans Xylose Galactose GlcNAc GlcA Disaccharide unit Core protein Linkage region Sulfate IdoA Large O-linked chains of as many as a hundred residues

18 Abnormalities in heparan sulfate biosynthesis is implicated in the human multiple exostoses syndrome

19

20 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.

21 Notch Serrate Delta Fringe O-fucose GlcNAc +

22 Providing structural components Cell walls Extracellular matrix Modifying protein properties Solubility Stability Directing trafficking of glycoconjugates Intracellular Extracellular Mediating and modulating cell adhesion Cell-cell interactions Cell-matrix interactions Mediating and modulating signaling Intracellular Extracellular Functions Extrinsic functions resulting from glycan-lectin interactions Intrinsic functions performed by glycans Glycans

23 III. O-mannosylation in muscular dystrophies

24 Normal muscleMuscular dystrophy Extracellular Intracellular Actin-filament Dystrophin   Dystroglycan Neurexin Agrin Laminin Membrane Basal Lamina Actin-filament Dystrophin   Dystroglycan Neurexin Agrin Laminin O-mannosyl glycans

25 Functions: III. O-mannosylation in muscular dystrophies Compromised O-mannosylation of dystroglycan causes severe muscle and brain abnormalities Example: Muscle-eye-brain disease: congenital muscular dystrophy, severe congenital myopia, hydrocephalus, mental retardation Muscle biopsy: Dystrophic changes Cranial MRI: Cerebellar hypoplasia Neuronal migration disorder Yoshida et al., Dev. Cell 2001

26 Muscular dystrophies associated with mutations in glycosyltransferase genes. ConditionGeneProtein functionClinical features Muscle-eye-brain disease (MEB) O-mannose-  -1,2-N- acetylglucosaminyltransferase (POMGnT1) O-mannosyl glycan synthesisSevere muscle weakness Mental retardation Epilepsy Neural migration disorder Ocular abnormalities Fukuyama congenital muscular dystrophy (FCMD) FukutinPutative glycosyltransferaseSevere proximal and axial weakness Mental retardation Epilepsy Neural migration disorder MDC1C and LGMD21Fukutin related protein (FRP)Putative glycosyltransferaseVariable proximal and axial muscle weakness Cardiomyopathy Walker Warburg syndrome (WWS) Protein O-mannosyltransferase 1 & 2 (POMT1 and POMT2) O-mannosyltransferaseSevere muscle weakness Death in infancy Absent psychomotor development Neural migration disorder Ocular abnormalities Rotated abdomen (rt) and twisted (tw) in Drosophila Protein O-mannosyltransferase 1 (POMT1) O-mannosyltransferaseDisrupted myogenesis Myodystrophy mouse (myd)LARGEPutative glycosyltransferaseMuscle weakness Neural migration disorder

27 IV. ABO blood groups (1900s, Landsteiner et al.) I O I A I B Alleles: Encode glycosyltransferases: Inactive GalNAc-transferase Gal-transferase Galactose GalNAc Fucose Glycans: Functions The glycan antigens are expressed on the surface of red blood cells and determine the compatibility in blood transfusions

28 Providing structural components Cell walls Extracellular matrix Modifying protein properties Solubility Stability Directing trafficking of glycoconjugates Intracellular Extracellular Mediating and modulating cell adhesion Cell-cell interactions Cell-matrix interactions Mediating and modulating signaling Intracellular Extracellular Structure Functions Glycans


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