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Essentials of Glycobiology May 1st, 2008 Ajit Varki

Essentials of Glycobiology May 1st, 2008 Ajit Varki. Lecture 11 Chapter 12 : Sialic Acids Chapter 32 : I-type Lectins. Major Glycan Classes in Vertebrate Cells. General Questions for Lecture 11. 1. Compare and contrast the structure of sialic acids with other vertebrate monosaccharides

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Essentials of Glycobiology May 1st, 2008 Ajit Varki

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  1. Essentials of GlycobiologyMay 1st, 2008Ajit Varki Lecture 11 Chapter 12 : Sialic Acids Chapter 32 : I-type Lectins

  2. Major Glycan Classes in Vertebrate Cells

  3. General Questions for Lecture 11 1. Compare and contrast the structure of sialic acids with other vertebrate monosaccharides 2. What advantages does sialic acid diversity provide in vertebrate systems? 3. What are the unique features of the sialic acid biosynthetic pathways in comparison to those of other vertebrate monosaccharides? 4. How would you determine if a previously unstudied organism contains sialic acids? 5. Contrast the addition of lpha2-6-linked sialic acids to O-GalNAc glycans and N-linked glycans and their recognition by sialic acid-binding lectins. 6. Why do plants and invertebrates that do not express sialic acids have sialic acid binding proteins? 7. There are now more than a dozen human Siglecs known.  Why were these and other sialic acid binding proteins not discovered until very recently? 8. Compare the potential function of Siglecs with inhibitory motifs in their cytosolic tails with those that can recruit activatory motifs 9. Why are Siglec homologs found primarily in "higher" animals 10. Why are some Siglecs evolving rapidly? 11. What changes in sialic acid biology occurred during human evolution?

  4. Two common “primary” sialic acids. • 1. Compare and contrast the structure of sialic acids with other vertebrate monosaccharides

  5. Biological Roles of Sialic Acids Structural/Physical Roles Influenza Malaria Cholera Helicobacter Mycoplasma Rotavirus SV40 virus Coronavirus Pertussis Tetanus etc. Siglecs Factor H Selectins L1CAM Laminins? Ligands for Extrinsic Receptors Ligands for Intrinsic Receptors EXTRINSIC RECEPTOR Molecular Mimicry SELF SELF M Meningococcus E.Coli K1 Gonococcus Campylobacter Trypanosoma Group B Streptococcus Etc. INTRINSIC RECEPTOR M = Micro-organism/Toxin SIALYLATED GLYCAN = SELF

  6. Natural Diversity in the Sialic Acids

  7. 2. What advantages does sialic acid diversity provide in vertebrate systems? Natural Diversity in the Sialic Acids R 8 O R 1 C O O R 7 R 9 O O 1 8 O R 2 9 O 6 2 R 5 7 4 3 5 O R 4 R1 = H, dissociation at physiological pH gives negative charge; lactones with -OH groups on same molecule or other glycans; lactams with a free amino group at C5; or tauryl group. R2 = H in free Sia; alpha linkage to Gal(3/4/6), GalNAc(6), GlcNAc(4/6), Sia (8/9) or 5-O-Neu5Gc; oxygen linked to C7 in 2,7-anhydro molecule; anomeric hydroxyl eliminated in Neu2en5Ac (double bond to C3) R4 = H, O-acetyl, anhydro to C8, Fuc, Gal R5 = Amino, N-acetyl, N-glycolyl, hydroxyl, N-acetimidoyl, N-glycolyl-O-acetyl, N-glycolyl-O-methyl, N-glycolyl-5-O-2-Neu5Gc R7 = H, O-acetyl, anhydro to C2; substituted by amino and N-acetyl in Leg R8 = H, O-acetyl, anhydro to C4, O-methyl, O-sulfate, Sia, Glc R9 = OH, O-acetyl, O-lactyl, O-phosphate, O-sulfate, Sia: OH substituted by H in Leg.

  8. Terminal, oligo-, and poly-sialic acids, and the enzymes that can degrade them

  9. Genes and pathways involved in the biology of sialic acids. • 3. What are the unique features of the sialic acid biosynthetic pathways in comparison to those of other vertebrate monosaccharides?

  10. Examples of terminal glycan sequences recognized by some sialic-acid-binding proteins. • 5. Contrast the addition of lpha2-6-linked sialic acids to O-GalNAc glycans and N-linked glycans and their recognition by sialic acid-binding lectins. • 6. Why do plants and invertebrates that do not express sialic acids have sialic acid binding proteins?

  11. Biological Roles of Sialic Acids Structural/Physical Roles Influenza Malaria Cholera Helicobacter Mycoplasma Rotavirus SV40 virus Coronavirus Pertussis Tetanus etc. Siglecs Factor H Selectins L1CAM Laminins? Ligands for Extrinsic Receptors Ligands for Intrinsic Receptors EXTRINSIC RECEPTOR Molecular Mimicry SELF SELF M Meningococcus E.Coli K1 Gonococcus Campylobacter Trypanosoma Group B Streptococcus Etc. INTRINSIC RECEPTOR M = Micro-organism/Toxin SIALYLATED GLYCAN = SELF

  12. 7. There are now more than a dozen human Siglecs known.  Why were these and other sialic acid binding proteins not discovered until very recently? Domain structures of the known Siglecs in humans and mice.

  13. Biological Interactions Involving Siglecs From: Crocker P, Paulson J. & Varki, A. Nature Reviews Immunol. 7:255-266, 2007.

  14. Signaling Responses Mediated by Siglecs • 8. Compare the potential function of Siglecs with inhibitory motifs in their cytosolic tails with those that can recruit activatory motifs From: Crocker P, Paulson J. & Varki, A. Nature Reviews Immunol. 7:255-266, 2007.

  15. Structural basis of Siglec binding to ligands. X-ray crystal structures of the V-set domains ofsialoadhesin (Sn) (A) and Siglec-7 (B) are shown complexed with sialic acid. (C,D) Molecular details of interactions of sialic acid with Sn and Siglec-7. Fig. 32.2

  16. Biological functions mediated by sialoadhesin: Interactions of sialoadhesin on macrophages with cells and pathogens. (Right) Red staining shows ring of sialoadhesin expressed by macrophages in marginal zone of spleen and green staining shows Siglec-H on the plasmacytoid dendritic cells

  17. Proposed Biological functions mediated by CD22: CD22 glycan-dependent homotypic interactions in equilibrium with CD22–BCR interactions.

  18. Biological functions mediated by myelin-associated glycoprotein (MAG)

  19. Proposed Biological functions mediated by CD33-related Siglecs

  20. 9. Why are Siglec homologs found primarily in "higher" animals? Chromosomal organization of CD33-related Siglec clusters in some rodents and primates • 10. Why are some Siglecs evolving rapidly?

  21. Proposed Evolutionary Chain of “Red Queen” Effects involving Sialic Acids and CD33-related-Siglecs Host sialic acids are evolving to adjust to the changes of Siglecs? Pathogens are evolving to utilize host sialic acids as receptors. Siglecs are evolving to evade sialylated pathogens that exploit them as receptors? Sialylated Pathogens Host sialic acids are evolving to evade pathogens that exploit them as receptors? Siglecs are evolving to adjust to the changes of host sialic acids? Pathogens expressing sialic acids are evolving to utilize Siglecs as receptors? Primary “Red Queen” Effect? Primary “Red Queen” Effect Secondary “Red Queen” Effect? Host Sialic acids CD33rSiglecs Pathogens Based on Varki &Angata Glycobiology 16:1R-27R, 2006. Modified by Takashi Angata: For Glycoforum/Glycowords

  22. Proposed Evolutionary Scenario for Multiple Human-Specific Changes in Sialic Acid Biology Varki A. Nature 446: 1023, 2007 • 11. What changes in sialic acid biology occurred during human evolution?

  23. Proposed Evolutionary Scenario for Multiple Human-Specific Changes in Sialic Acid Biology Varki A. Nature 446: 1023, 2007

  24. Proposed Evolutionary Scenario for Multiple Human-Specific Changes in Sialic Acid Biology CMAH SIGLEC12 ST6GAL1 SIGLEC7 SIGLEC9 SIGLEC6 SIGLEC11 SIGLEC5/14 SIGLEC13 SIGLEC1 DELETION AMINO ACID CHANGE EXPRESSION CHANGE GENE CONVERSION Varki A. Nature 446: 1023, 2007

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