discussion 8 hyaluronan, sulfated glycosaminoglycans & glycosaminoglycan binding proteins
TRANSCRIPT
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Discussion 8
Hyaluronan, Sulfated Glycosaminoglycans & Glycosaminoglycan Binding Proteins
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GalNAc GlcA
Chondroitin/Dermatan
Sulfate
GlcNAc GlcA
Hyaluronan
6S 4S4S4S6S 4S 4S
2S
Glycosaminoglycans (GAG)
IdoA
6S 6S
NS NS3S 2S NS
GlcNAc GlcA
IdoAHeparin/Heparan Sulfate
6S 6S 6S 6S 6S
GalNAc Gal
KeratanSulfate
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6S 6S
NS NS3S 2S NS
IdoA
Sulfated Glycosaminoglycans
6S 6S 6S 6S 6S
HONO
GalNAc GlcA
6S 4S4S4S6S 4S 4S
2S
IdoA
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Cytosol Golgi
Ser
Galactosyltransferases
Glucuronosyltransferase I
UDP-
Nucleotide sugartransporters
n
GAG Synthases
Sulfated GAG Biosynthesis
UDP-
UDP- UDP-
UDP-
UDP-GlcDehydrogenase
UDP-
UDP-
UDP-GlcADecarboxylase
UDP-
Xylosyltransferases
UDP- UDP-
S S
Sulfotransferases
SS
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Biosynthesis of a Heparan Sulfate Chain
NSNS NSNS
6S6S
GalGalGlcA
CopolymeraseComplex
EXT1/EXT2
GlcNAc N-deacetylaseN-sulfotransferases(NDST) (4 isozymes)
3S
GlcNH2/S3-O-sulfotransferases(3OST) (7 isozymes)
2S
Uronic acid2-O-sulfotransferase
IdoA
Epimerase
GlcNAc/S6-O-sulfotransferases(6OST) (3+ isozymes)
6S GlcNAc
EXTL3
Xyl
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Proteoglycan Turnover
Plasma membrane
Endocytosis
Step3exoglycosidasesulfatase
Golgi
HS oligosaccharide(~10 kDa)
HS oligosaccharide(~5 kDa)
ProteolyticSheddingEndo-6-sulfatase
HeparanaseProtease
Heparanase
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Aggrecan Family
Chondroitin sulfate
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Interstitial ProteoglycansSLRPs - Small Leucine Rich Proteoglycans
Gene Knockouts
Decorin(single CS chain)
• Fragile skin• Thin dermis• Increased resistance to
Borrelia burgdorfei
Biglycan(two CS chains)
• Decrease in bone mass and dentin mineralization
• Fewer osteoblasts• Mild muscular dystrophy
Fibromodulin(keratan sulfate)
• Ectopic tendon ossification
Lumican (keratan sulfate)
• Corneal opacification
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Perlecan - Basement Membrane Proteoglycan
LDLreceptor-like
repeats
Lamininrepeats
Ig-like repeats Laminin &EGF motifs
467 KDa
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Cell-BindingDomain
TM
C1
C2
V
Glypicans GPI anchored proteins
6 members
Syndecans Type I Membrane Proteins
4 members
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Hyaluronan
n ~ 50,000
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Hyaluronan as a Scaffold
HyaluronicAcid
Aggrecan
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A B C
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OO
OOH
NSO3-
OSO3-
OCOO-
OH
OSO3-
OO
OOSO3
-
NSO3-
±OSO3-
O
COO-
OH
OH
OOH
NAc
OSO3-
OOO
O
OOH
NSO3-
OSO3-
OCOO-
OH
OSO3-
OO
OOH
NSO3-
OSO3-
OCOO-
OH
OSO3-
OOH
NSO3-
OH
OO
Heparan Sulfate Structure is Complex
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Antithrombin-Heparin
OO
OOH
NHSO3-
OSO3-
OCOO-OH
OSO3-
OO
OOSO3
-
NHSO3-
±OSO3-
O
COO-
OH
OH
OOH
NAc
OSO3-
OO
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FGF
Heparan sulfate
FGF
Any Cell
Coreceptors
Heparan sulfate
Depots and Gradients
Hh
WntBasement
Membranes andOther ECMs
MatrixProteins
Col Fn
Heparan Sulfate Proteoglycans
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FGF-Heparin Hexasaccharide
Crystal structure shows surface binding
119KRTGQYKLGSKTGPGQK135
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FGF FGF
Mulloy & Linhardt (2001) COSB 11:623
• Symmetric structure
• Heparin interacts with both ligands and receptors
• Two heparin oligosaccharides present in crystal
Heparin
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6S
NS
6S
NS
6S
NS2S 2S 2S
6S
NS
6S
NS2S 2S
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Heparin versus Heparan Sulfate
The difference between heparin and heparan sulfate is quantitative not qualitative
6S6S
NS NS3S 2S NS
2S
6S
NS