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ESSENTIALS OF GLYCOBIOLOGY Lecture 30 May 18, 2004 Marilynn Etzler Section of Molecular and Cellular Biology University of California Davis, CA 95616 ([email protected]) FREE GLYCANS AND THEIR ROLES AS SIGNALING MOLECULES LECTURE OUTLINE • Background • Oligosaccharide signals trigger the initiation of the plant defense response • Nod factor signals initiate the nitrogen-fixing Rhizobium-legume symbiosis • Chitin oligosaccharide signals in plant defense and early animal development • Other oligosaccharide signals in early plant and animal development • Pattern recognition receptors and innate immunity •Background: Potential of oligosaccharides as signals: 1) Variety of linkages between monomers enables a large number of conformational variations. Portion of Table shown in Lecture 1: Macromolecule Building block Protein Nucleic Acid Carbohydrate Amino acids Nucleotides Hexoses Possible variations in a trimer 6 6 1,056 to 27,648 2) Many hydroxyls available for modification. Basic elements of signaling system: Signal Receptor Transduction mechanism Response • Oligosaccharide Signals Trigger the Initiation of the Plant Defense Response Plant Defense Responses: Pathogen Pathogen Elicitor Elicitor Cell wall Plasma membrane Early Plant Responses Changes in ion fluxes Oxidative burst H2O2 and O2 Activation of early defense-related genes Phytoalexin production Structural changes in cell walls The first oligosaccharide signal was identified in the fungus, Phytophthora megasperma, a fungal pathogen of soybean. Isolated from cell walls Elicits phytoalexin production in soybean seedlings Structure confirmed by chemical synthesis 3 3 Hepta--glucoside 6 6 6 6 Relative Activities of Oligo--Glucosides 3 6 Relative Elicitor Activity 3 6 6 Relative Binding Activity 1000 1000 270 93 6 3 3 6 3 6 3 6 6 3 1.2 6 6 6 6 = reduced glucose 1.3 • Nod factor signals initiate the nitrogen-fixing Rhizobium-legume symbiosis Rhizobia CH2O R 5 O R O R O R4' NR 1 HO R2 O NH CO CH3 R5' R7 R5 3 O O 4 R3' OR 6 CH2 O CH2OH O HO n NH CO O R 7 CH3 NOD Factor R3 O Flavonoids Root hair deformation Infection thread formation GENERIC STRUCTURE OF NOD FACTORS R5 R6 O O CH 2 R4 O R3 CH 2OH O O R2 O HO N R1 CH 2 O O HO NH C=O CH 3 n R1 = H, Methyl R5 = H, Ac R2 = C16:2, C16:3 C18:1, C18:3, C18:4 C20:3, C20:4 R6 = H, Ac, SO4 Fuc AcFuc MeFuc R3 = H, Cb R4 = H, Cb O O R7 NH C=O CH 3 R7 = H Glycerol n=1-4 • Chitin oligosaccharide signals in plant defense and early animal development Elicit alkalinization of medium of tomato cell cultures Biological activity (nanomolar) 0.1 4 4 4 4 0.1 4 4 4 50 4 4 4 100,000 >1,000,000 Evidence for chitin oligosaccharide signaling in early animal development: In Xenopus laevis the developmentally regulated protein, DG42, is homologous to Nod C, the enzyme that synthesizes the chitin backbone of the Nod factors in rhizobia. DG42 is only expressed between the gastrula and neurulaation stages. DG42 can direct the synthesis of chitin oligosaccharides in vitro. Chitin oligosaccharides can be synthesized by extracts of gastrulation stage embryos of cyprinid fishes (zebra fish and carp). Microinjection of fertilized eggs with antibodies against DG42 leads to severe defects in trunk and tail development. • Other oligosaccharide signals in early plant and animal development Oligogalacturonides - isolated from plant cell walls 4 4 4 4 4 4 4 4 4 Serve as signals in both defense and in plant development DEFENSE: Usually need DP of 10-14 to elicit phytoalexin accumulation. DEVELOPMENT: Different DP elicit different responses. = Galacturonic acid DP = degree of polymerization Xyloglucan nonasaccharide: 2 2 6 4 6 6 4 4 Concentrations of 10-8 M inhibit auxin-induced elongation of stem fragments. Hyaluronan fragments: 3 4 3 4 n 3 Activate antigen presenting cells and other proinflammatory responses, signal cell motility and adhesion • Innate immunity Dependent on proteins and phagocytic cells that recognize conserved features of pathogens that are absent in the host. Found in vertebrates, invertebrates and plants. Pattern recognition receptors Recognize pathogen-associated immunostimulants Examples of repeating patterns that often occur on pathogen surfaces Chitin, glucan and other polysaccharides in cell walls of fungi Peptidoglycan cell wall and flagella of bacteria Lipopolysaccharide on Gram-negative bacteria Teichoic acids on Gram-positive bacteria Such repeating patterns called PAMPS (Pathogen-Associated Molecular Patterns) Pathogen associated immunostimulants Pathogen Pattern recognition receptor Macrophage plasma membrane When signal binds to the receptor, it causes the rearrangement of actin filaments as well as the transcription of new genes. The pathogen is endocytosed Actin rearrangement Actin Acid hydrolases Lysozyme Phagosome Transcription of target genes Lysosome Pattern recognition receptors Distinguish self from conserved microbial structures. Drosophila – identified Toll receptors Mammals – identified Toll-like receptors (TLRs) Leucine rich repeat (LRR) domain Indirectly associated with binding PAMPs May be part of receptor complex Membrane TIR domain Interacts with adaptor protein PLANTS Angiosperms FUNGI ANIMALS Vertebrates Gymnosperms Urochordates Insects Chordates Arthropods Mollusks Nematodes Brown algae Coelenterates Red algae Green algae Sponges Slime molds Unicellular PROTOZOA Yeasts EUKARYOTES Mosses Liverworts Multicellular Echinoderms Ferns Ancestral Prokaryotes Adapted from Figure 1-38, Molecular Biology of the Cell, 3rd ed., Garland Publishing, Inc. Pathogen Perception and Defense Systems Plants Legumes Animals Mammals Insects Last common ancestor may have used a related TLR for pathogen recognition