Transcript Lecture12Terminal

Essentials of Glycobiology
May 5th., 2008
Ajit Varki
Lecture 12
Chapter 13. Sequences Common to Different Glycan Classes
Chapter 33. Galectins
Major Glycan Classes in Vertebrate Cells
Shared Terminii in Different Glycan Classes of Vertebrate Cells
Essentials Second Edition Symbols
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?
FIGURE 13.2. Terminal GlcNAc residues are usually
galactosylated in Vertebrate Cells
3. Compare and contrast "LacNAc" and "LacdiNAc" units
"LacNAc"
FIGURE 13.3. Poly-N-acetyllactosamine chains are
found on N-glycans, O-glycans, and glycolipids
“Polyllactosamine” Chains
N-acetyllactosamine
Unit
FIGURE 13.4. i and I antigen synthesis
Adult
Embryonic
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!
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”
FIGURE 13.8. Synthesis of H (O), A, and B blood group determinants
“Universal
Donor”
“O
”
“A”
Anti-B
“AB”
“Universal
Acceptor”
No
Antibodies
Anti-A
Anti- B
“B”
Anti-A
O-glycans
Glycosphingolipids
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
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.
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
Anti-A
Anti- B
“B”
Anti-A
FIGURE 13.12. Biosynthesis of antigens of the P blood group system: Pk, P, and P1.
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?
E.coli
Parvovirus
B19
E.coli
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.
Alpha-Gal Epitope
Anti-alpha Gal
Antibodies
Owl Word Monkeys
Apes & Humans
-
+
Other Mammals
+
-
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.
FIGURE 13.16. Synthesis of the human Sda or mouse CT
antigen and the glycolipid GM2
FIGURE 13.17. Synthesis of glycoproteins and glycolipids bearing terminal α2-3 sialic
acid transferred by the ST3Gal family of sialyltransferases
FIGURE 13.18. Synthesis of α2-6 sialic acids (see Chapters 9 and 10)
Tumor
Antigen
Cosmc
FIGURE 13.19. Structure and synthesis of polysialic acid on N-glycans
Embryonic
Neural
Plasticity
Adult
FIGURE 13.20. Structure and synthesis of polysialic acid on glycolipids.
Neural
Functions?
CD57 NK cell Marker
Antigen in Myeloma
P0 Ligand?
Cellular Interactions
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).
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.
7.
How do galectins achieve high-affinity binding to cell surface glycans?
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?
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?
FIGURE 33.5. A list of known and putative functions and biological activities of
galectins toward cells in the immune system.
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?