Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated?

Rosenberg, Robert D.; Shworak, Nicholas W.; Liu, Jian; Schwartz, John J.; Zhang, Lijuan

doi:10.1172/jci119377

Cited by 363 publications

(328 citation statements)

References 87 publications

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“…HS play critical roles in a variety of biological interactions, including assisting viral infection, regulating blood coagulation and embryonic development, suppressing tumor growth, and controlling the eating behavior of mice by interacting with specific regulatory proteins (1)(2)(3)(4)(5). HS is initially synthesized as a copolymer of glucuronic acid and N-acetylated glucosamine by D-glucuronyl and N-acetyl-D-glucosaminyl transferase, followed by various modifications (6).…”

Section: -O-sulfotransferase Isoform 3 (3-ost-3) and It Provides Bimentioning

confidence: 99%

“…The determined molecular mass for fraction D was very close to the theoretical value (1950.1 Da) for a heptasulfated octasaccharide with one N-acetylated glucosamine residue (⌬UA(UA) 3 (GlcN) 3 GlcNAc(SO 3 H) 7 , C 50 H 78 O 62 N 4 S 7 ). 2 We also determined the molecular mass of fraction D by using MALDI-MS. MALDI-MS requires that a complex between fraction D and a synthetic peptide (Arg-Gly) 19 -Arg be formed (32). After subtracting the contribution of the protonated peptide, the molecular mass of fraction D was calculated to be 1951.2 Da (spectrum not shown).…”

Section: Isolation Of the Gd-binding Octasaccharidementioning

confidence: 99%

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Characterization of a Heparan Sulfate Octasaccharide That Binds to Herpes Simplex Virus Type 1 Glycoprotein D

Liu

Shriver

Pope

et al. 2002

Journal of Biological Chemistry

153

116

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Herpes simplex virus type 1 utilizes cell surface heparan sulfate as receptors to infect target cells. The unique heparan sulfate saccharide sequence offers the binding site for viral envelope proteins and plays critical roles in assisting viral infections. A specific 3-O-sulfated heparan sulfate is known to facilitate the entry of herpes simplex virus 1 into cells. The 3-O-sulfated heparan sulfate is generated by the heparan sulfate D-glucosaminyl-3-O-sulfotransferase isoform 3 (3-OST-3), and it provides binding sites for viral glycoprotein D (gD). Here, we report the purification and structural characterization of an oligosaccharide that binds to gD. The isolated gDbinding site is an octasaccharide, and has a binding affinity to gD around 18 M, as determined by affinity coelectrophoresis. The octasaccharide was prepared and purified from a heparan sulfate oligosaccharide library that was modified by purified 3-OST-3 enzyme. The molecular mass of the isolated octasaccharide was determined using both nanoelectrospray ionization mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometry. The results from the sequence analysis suggest that the structure of the octasaccharide is a heptasulfated octasaccharide. The proposed structure of the octasaccharide is ⌬UA-GlcNSIdoUA2S-GlcNAc-UA2S-GlcNS-IdoUA2S-GlcNH 2 3S6S. Given that the binding of 3-O-sulfated heparan sulfate to gD can mediate viral entry, our results provide structural information about heparan sulfate-assisted viral entry.Heparan sulfates (HS), 1 highly sulfated polysaccharides, are present on the surface of mammalian cells and in the extracellular matrix in large quantities. HS play critical roles in a variety of biological interactions, including assisting viral infection, regulating blood coagulation and embryonic development, suppressing tumor growth, and controlling the eating behavior of mice by interacting with specific regulatory proteins (1-5). HS is initially synthesized as a copolymer of glucuronic acid and N-acetylated glucosamine by D-glucuronyl and N-acetyl-D-glucosaminyl transferase, followed by various modifications (6). These modifications include C 5 -epimerization of glucuronic acid to form iduronic acid residues, 2-O-sulfation of iduronic and glucuronic acid, N-deacetylation and N-sulfation of glucosamine, as well as 6-O-sulfation and 3-O-sulfation of glucosamine. Numerous HS biosynthetic enzymes have been cloned and characterized (for review, see Esko and Lindahl (7)).The specific sulfated saccharide sequences play critical roles in determining the functions of HS. A recent report suggests that the expression levels of various isoforms of each class of HS biosynthetic enzyme contribute to the synthesis of specific saccharide sequences in specific tissues (8). HS N-deacetylase/ N-sulfotransferase, 3-O-sulfotransferase, and 6-O-sulfotransferase are present in multiple isoforms, and each isoform is believed to recognize the saccharide sequence around the modification site to generate a specific sulfated saccharid...

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Section: -O-sulfotransferase Isoform 3 (3-ost-3) and It Provides Bimentioning

confidence: 99%

Section: Isolation Of the Gd-binding Octasaccharidementioning

confidence: 99%

Characterization of a Heparan Sulfate Octasaccharide That Binds to Herpes Simplex Virus Type 1 Glycoprotein D

Liu

Shriver

Pope

et al. 2002

Journal of Biological Chemistry

153

116

View full text Add to dashboard Cite

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“…The cytoplasmic tails of syndecans associate with the cytoskeleton through a variety of linker molecules that provide the structures required to distribute force throughout the cell. Of the glypicans, glypican-1 is the only one expressed on EC [4]. The glypican ectodomain is thought to form a compact globular tertiary structure with three to four GAG attachment sites closer to the membrane that are substituted exclusively with HS.…”

Section: Introductionmentioning

confidence: 99%

The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress

Pahakis¹,

Kosky²,

Dull³

et al. 2007

Biochemical and Biophysical Research Communications

343

338

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The surface of endothelial cells is decorated with a wide variety of membrane-bound macromolecules that constitute the glycocalyx. These include glycoproteins bearing acidic oligosaccharides with terminal sialic acids (SA), and proteoglycans with their associated glycosaminoglycan that include: heparan sulfate (HS), chondroitin sulfate (CS) and hyaluronic acid (HA). In this study enzymes were used to selectively degrade glycoclyx components from the surface of bovine aortic endothelial cells and the effects of these alterations on fluid shear-induced nitric oxide (NO) and prostacyclin (PGI 2 ) production were determined. Depletion of HS, HA and SA, but not CS, blocked shear-induced NO production. Surprisingly, the same enzyme depletions that blocked NO production had no influence on shear-induced PGI 2 production. The results may be interpreted in terms of a glypicancaveolae-eNOS mechanism for shear-induced NO transduction, with PGI 2 being transduced in basal adhesion plaques that sense the same reaction stress whether the glycocalyx is intact or not.

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“…HLGAGs are expressed on animal cell surfaces, in basement membranes and mast cell granules and play roles in blood coagulation, cellular proliferation, and interactions with fibroblast growth factors [1][2][3]. Sequence determination, including localization of sulfate groups on HLGAGs, is of significant interest, as their biological activities are believed to be expressed through patterns of sulfation and uronic acid epimerization [4,5].…”

mentioning

confidence: 99%

Competing fragmentation processes in tandem mass spectra of heparin-like glycosaminoglycans

Naggar

Costello

Zaia

2004

J. Am. Soc. Mass Spectrom.

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Heparin-like glycosaminoglycans (HLGAGs) are highly sulfated, linear carbohydrates attached to proteoglycan core proteins and expressed on cell surfaces and in basement membranes. These carbohydrates bind several families of growth factors and growth factor receptors and act as coreceptors for these molecules. Tandem mass spectrometry has the potential to increase our understanding of the biological significance of HLGAG expression by providing a facile means for sequencing these molecules without the need for time-consuming total purification. The challenge for tandem mass spectrometric analysis of HLGAGs is to produce abundant ions derived via glycosidic bond cleavages while minimizing the abundances of ions produced from elimination of the fragile sulfate groups. This work describes the competing fragmentation pathways that result from dissociation of high negative charge state ions generated from HLGAGs. Glycosidic bond cleavage ion formation competes with losses of equivalents of H 2 SO 4 , resulting in complex ion patterns. For the most highly sulfated structure examined, an octasulfated tetramer, an unusual loss of charge from the precursor ion was observed, accompanied by low abundance ions originating from subsequent backbone cleavages. These results demonstrate that fragmentation processes competing with glycosidic bond cleavages are more favored for highly sulfated HLGAG ions. In conclusion, reduction of charge-charge repulsions, such as is achieved by pairing the HLGAG ions with metal cations, is necessary in order to minimize the abundances of ions derived via fragmentation processes that compete with glycosidic bond cleavages. Sequence determination, including localization of sulfate groups on HLGAGs, is of significant interest, as their biological activities are believed to be expressed through patterns of sulfation and uronic acid epimerization [4,5].HLGAGs have traditionally proven difficult to analyze using mass spectrometry. Efforts to analyze these molecules using fast atom bombardment MS resulted in the observation of losses of SO 3 and NaSO 3 from the precursor ion, in addition to glycosidic bond cleavage ions [6 -10]. The poor sensitivity, relative to that achieved for peptides of comparable size, and lack of an intact precursor ion meant that tandem MS was not a viable analysis option when FAB ionization was employed. Although HLGAGs produce weak signals by matrix-assisted laser desorption/ionization (MALDI), much more abundant ions are detected from complexes between these molecules and a basic peptide [11][12][13]. In conjunction with enzymatic and/or chemical degradation, this MALDI sample preparation technique has been effectively used to sequence highly purified HLGAGs [14 -17]. Because the ions are detected in the positive mode, however, the charge is carried by the basic peptide and tandem MS of the HLGAG is not possible.Because HLGAGs and other sulfated carbohydrates produce abundant negative ions using electrospray ionization (ESI) without requiring basic peptide complexation [18...

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Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated?

Cited by 363 publications

References 87 publications

Characterization of a Heparan Sulfate Octasaccharide That Binds to Herpes Simplex Virus Type 1 Glycoprotein D

Characterization of a Heparan Sulfate Octasaccharide That Binds to Herpes Simplex Virus Type 1 Glycoprotein D

The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress

Competing fragmentation processes in tandem mass spectra of heparin-like glycosaminoglycans

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