Essentials of Glycobiology May 5th., 2008 Ajit Varki

1. Essentials of GlycobiologyMay 5th., 2008Ajit Varki Lecture 12 Chapter 13. Sequences Common to Different Glycan Classes Chapter 33. Galectins

2. Major Glycan Classes in Vertebrate Cells

4. Shared Terminii in Different Glycan Classes of Vertebrate Cells

5. Essentials Second Edition Symbols

6. General Questions for Lecture 11 1. Propose a function for the allelic variation observed in the ABO blood group system. If non-primates do not express the ABO locus due to evolutionary loss of the gene, how would this affect your answer? 2. Hyperacute (graft) rejection occurs after transplantation of organs from non-human donors into humans and results from an immediate reaction of circulating anti-GalGal antibodies with the transplanted tissue. Suggests ways to modify the donor or acceptor to prevent HAR. 3. Compare and contrast "LacNAc" and "LacdiNAc" units. How does the presence of these terminal disaccharides affect the addition of sialic acid and fucose? 4. Based on what you know about terminal structures on FSH and LH, propose several glycan-based mechanisms that could account for infertility in humans. 5. Certain strains of E. coli bind to P-blood group antigens and cause urinary tract infections. What evolutionary advantage might exist for retaining the transferases for a deleterious glycan? 6. Why do changes in glycan branching pathways and sialylation have the potential to impact galectin function? 7. How do galectins achieve high-affinity binding to cell surface glycans? 8. How do you explain the finding that galectins are not routinely found in large amounts in body fluids, even though they are soluble secreted proteins? 9. Explain how a galectin could act as a receptor for microbial infection 10. How do galectins send signals through cell surface receptors?

7. 3. Compare and contrast "LacNAc" and "LacdiNAc" units FIGURE 13.2. Terminal GlcNAc residues are usually galactosylated in Vertebrate Cells "LacNAc"

8. “Polyllactosamine” Chains FIGURE 13.3. Poly-N-acetyllactosamine chains are found on N-glycans, O-glycans, and glycolipids N-acetyllactosamine Unit

9. FIGURE 13.4. i and I antigen synthesis Adult Cold-dependent agglutinating antibodies (cold agglutinins) in patients with acquired hemolytic anemia (see Chapter 43). Cold agglutinin antibodies react with red blood cells of most blood donors Including patient’s own cells! Embryonic

10. FIGURE 13.5. Type-1 and -2 H, A, and B antigens that form the O (H), A, and B blood group determinants on N- and O-glycans “O” “A” “B”

11. FIGURE 13.8. Synthesis of H (O), A, and B blood group determinants “Universal Donor” “A” “O” Anti-B “Universal Acceptor” “AB” No Antibodies “B” Anti-A Anti- B Anti-A

12. O-glycans

13. Glycosphingolipids

15. FIGURE 13.10. Type-1 and -2 Lewis determinants • 3. How does the presence of terminal disaccharides affect the addition of sialic acid and fucose? Some of these are Ligands for Selectins

16. FIGURE 13.11. Lewis blood groups based on Type 1 LacNAc • Type-1 Lewis blood group determinants on glycoproteins and glycolipids (R) are characterized by the presence or absence of the Secretor locus α1-2FucT and the Lewis locus α1-3/α1-4FucT.

17. 3. Propose a function for the allelic variation in the ABO blood group system. If non-primates do not express the ABO locus due to evolutionary loss of the gene, how would this affect answer? “A” “O” Anti-B “AB” No Antibodies “B” Anti-A Anti- B Anti-A

18. FIGURE 13.12. Biosynthesis of antigens of the P blood group system: Pk, P, and P1. E.coli Parvovirus B19 E.coli 5. Certain strains of E. coli bind to P-blood group antigens and cause urinary tract infections. What evolutionary advantage might exist for retaining transferases for a deleterious glycan?

19. 2. Hyperacute (graft) rejection occurs after transplantation of organs from non-human donors into humans and results from an immediate reaction of circulating anti-GalGal antibodies with the transplanted tissue. Suggests ways to modify the donor or acceptor to prevent HAR.

21. FIGURE 13.15. Structure and synthesis of N-glycans bearing terminal N-acetylgalactosamine (GalNAc), including sulfated GalNAc on pituitary hormones lutropin (LH) and thyrotropin (TSH). 3. Compare and contrast "LacNAc" and "LacdiNAc" units "LacdiNAc" "LacNAc" 4. Based on what you know about terminal structures on FSH and LH, propose several glycan-based mechanisms that could account for infertility in humans.

22. FIGURE 13.16. Synthesis of the human Sda or mouse CT antigen and the glycolipid GM2

23. FIGURE 13.17. Synthesis of glycoproteins and glycolipids bearing terminal α2-3 sialic acid transferred by the ST3Gal family of sialyltransferases

24. FIGURE 13.18. Synthesis of α2-6 sialic acids (see Chapters 9 and 10) Tumor Antigen Cosmc

25. FIGURE 13.19. Structure and synthesis of polysialic acid on N-glycans Embryonic Neural Plasticity Adult

26. FIGURE 13.20. Structure and synthesis of polysialic acid on glycolipids. Neural Functions?

27. CD57 NK cell Marker Antigen in Myeloma P0 Ligand? Cellular Interactions

28. FIGURE 13.22. Synthesis of keratan sulfate. Different 6-O-sulfotransferases (SulfoT) transfer sulfate to 6-position of Gal and GlcNAc in poly-N-acetyllactosamine chains. Is Ks and Glycosaminoglycan (GAG)? Human Macular Corneal Dystrophy KS is attached to proteins (R) via an N-glycan (KS type I) or an O-glycan (KS type II).

29. FIGURE 33.3. (a) Ribbon diagram of crystal structure of human galectin-1, complexed with lactose. Homodimer shown with each monomer colored differently and orthogonal views are presented. The subunit interface is based on interactions between the carboxy- and amino-terminal domains of each subunit. (b) Interactions between key amino acid residues within the CRD of galectin-1 when lactose is bound (left panel) and when no sugar is bound (right panel). (c) Primary sequence of human galectin-1 with the numbered residues corresponding to those highlighted in the crystal structure above.

30. 7. How do galectins achieve high-affinity binding to cell surface glycans?

31. FIGURE 33.2. Possible biosynthetic routes for galectins in animal cells. • 8.How do you explain the finding that galectins are not routinely found in large amounts in body fluids, even though they are soluble secreted proteins?

32. FIGURE 33.4. Functional interactions of galectins with cell-surface glycoconjugates and extracellular glycoconjugates can lead to cell adhesion and signaling. Interactions with intracellular ligands may also contribute to regulation of intracellular pathways. 10.How do galectins send signals through cell surface receptors?

33. FIGURE 33.5. A list of known and putative functions and biological activities of galectins toward cells in the immune system.

34. General Questions for Lecture 11 1. Propose a function for the allelic variation observed in the ABO blood group system. If non-primates do not express the ABO locus due to evolutionary loss of the gene, how would this affect your answer? 2. Hyperacute (graft) rejection occurs after transplantation of organs from non-human donors into humans and results from an immediate reaction of circulating anti-GalGal antibodies with the transplanted tissue. Suggests ways to modify the donor or acceptor to prevent HAR. 3. Compare and contrast "LacNAc" and "LacdiNAc" units. How does the presence of these terminal disaccharides affect the addition of sialic acid and fucose? 4. Based on what you know about terminal structures on FSH and LH, propose several glycan-based mechanisms that could account for infertility in humans. 5. Certain strains of E. coli bind to P-blood group antigens and cause urinary tract infections. What evolutionary advantage might exist for retaining the transferases for a deleterious glycan? 6. Why do changes in glycan branching pathways and sialylation have the potential to impact galectin function? 7. How do galectins achieve high-affinity binding to cell surface glycans? 8. How do you explain the finding that galectins are not routinely found in large amounts in body fluids, even though they are soluble secreted proteins? 9. Explain how a galectin could act as a receptor for microbial infection 10. How do galectins send signals through cell surface receptors?