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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 - PowerPoint PPT Presentation
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Essentials of Glycobiology
May 1st, 2008
Ajit VarkiLecture 11
Chapter 12 : Sialic Acids
Chapter 32 : I-type Lectins
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?
Two common “primary” sialic acids.
1. Compare and contrast the structure of sialic acids with other vertebrate monosaccharides
Biological Roles of Sialic Acids
EXTRINSIC RECEPTOREXTRINSIC RECEPTOR
M
Ligands forIntrinsic
Receptors
SiglecsFactor HSelectinsL1CAM
Laminins?
SIALYLATED GLYCAN =
M = Micro-organism/Toxin
InfluenzaMalariaCholera
HelicobacterMycoplasma
RotavirusSV40 virus
CoronavirusPertussis
Tetanus etc.
Ligands for Extrinsic
Receptors
Structural/Physical Roles
MolecularMimicry Meningococcus
E.Coli K1Gonococcus
CampylobacterTrypanosoma
Group BStreptococcus
Etc.
SELFSELF
INTRINSIC RECEPTORINTRINSIC RECEPTOR
SELF
O
COO
O
O
OO
O 1
2
345
69 8
7
R1
R2
R4
R7R8
R9
R5
Natural Diversity in the Sialic Acids
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.
2. What advantages does sialic acid diversity provide in vertebrate systems?
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?
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?
Biological Roles of Sialic Acids
EXTRINSIC RECEPTOREXTRINSIC RECEPTOR
M
Ligands forIntrinsic
Receptors
SiglecsFactor HSelectinsL1CAM
Laminins?
SIALYLATED GLYCAN =
M = Micro-organism/Toxin
InfluenzaMalariaCholera
HelicobacterMycoplasma
RotavirusSV40 virus
CoronavirusPertussis
Tetanus etc.
Ligands for Extrinsic
Receptors
Structural/Physical Roles
MolecularMimicry Meningococcus
E.Coli K1Gonococcus
CampylobacterTrypanosoma
Group BStreptococcus
Etc.
SELFSELF
INTRINSIC RECEPTORINTRINSIC RECEPTOR
SELF
Domain structures of the known Siglecs in humans and mice.
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?
From: Crocker P, Paulson J. & Varki, A. Nature Reviews Immunol. 7:255-266, 2007.
Biological Interactions Involving Siglecs
From: Crocker P, Paulson J. & Varki, A. Nature Reviews Immunol. 7:255-266, 2007.
Signaling Responses Mediated by Siglecs8. Compare the potential function of Siglecs with inhibitory motifs in their cytosolic tails with those that can recruit activatory motifs
Fig. 32.2
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.
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
Proposed Biological functions mediated by CD22: CD22 glycan-dependent homotypic interactions in equilibrium with CD22–BCR interactions.
Chromosomal organization of CD33-related Siglec clusters in some rodents and primates
9. Why are Siglec homologs found primarily in "higher" animals?
10. Why are some Siglecs evolving rapidly?
Proposed Evolutionary Chain of “Red Queen” Effects involving Sialic Acids and CD33-related-Siglecs
Host sialic acids are evolving to evade pathogens
that exploit them as receptors?
Host Sialic acidsPathogens
Pathogens are evolving to utilize host sialic acids
as receptors.
CD33rSiglecs
Siglecs are evolving to adjust to the changes
of host sialic acids?
Host sialic acids are evolving to adjust to the changes
of Siglecs?
SialylatedPathogens
Pathogens expressing sialic acids are evolving to utilize Siglecs as receptors?
Siglecs are evolving to evade sialylated pathogens
that exploit them as receptors?
Based on Varki &Angata Glycobiology 16:1R-27R, 2006.Modified by Takashi Angata: For Glycoforum/Glycowords
PrimaryPrimary““Red Red
QueenQueen””EffectEffect
PrimaryPrimary““Red Red
QueenQueen””Effect?Effect?
SecondarySecondary““Red Red
QueenQueen””Effect?Effect?
Proposed Evolutionary Scenario for Multiple Proposed Evolutionary Scenario for Multiple Human-Specific Changes in Sialic Acid BiologyHuman-Specific Changes in Sialic Acid Biology
Varki A. Nature 446: 1023, 2007
11. What changes in sialic acid biology occurred during human evolution?
Proposed Evolutionary Scenario for Multiple Proposed Evolutionary Scenario for Multiple Human-Specific Changes in Sialic Acid BiologyHuman-Specific Changes in Sialic Acid Biology
Varki A. Nature 446: 1023, 2007
Proposed Evolutionary Scenario for Multiple Proposed Evolutionary Scenario for Multiple Human-Specific Changes in Sialic Acid BiologyHuman-Specific Changes in Sialic Acid Biology
Varki A. Nature 446: 1023, 2007
ST6GAL1ST6GAL1
SIGLEC7SIGLEC7SIGLEC9SIGLEC9
DELETIONAMINO ACID CHANGEEXPRESSION CHANGE
GENE CONVERSION
SIGLEC6SIGLEC6SIGLEC11SIGLEC11SIGLEC5/14SIGLEC5/14SIGLEC13SIGLEC13
CMAHCMAH
SIGLEC12SIGLEC12
SIGLEC1SIGLEC1