Extended N-Sulfated Domains Reside at the Nonreducing End of Heparan Sulfate Chains

Staples, Gregory O.; Shi, Xiaofeng; Zaia, Joseph

doi:10.1074/jbc.m110.101592

Cited by 48 publications

(61 citation statements)

References 48 publications

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“…The highly sulfated domain, also known as the S-domain, contributes to the binding to growth factors and chemokines. This domain contains the disaccharide repeating units -IdoUAϮ2S-GlcNS6S-and -GlcUA-GlcNS6S- (24). Although the IdoUAϮ2S-GlcNS6S linkage is known to be resistant to heparanase action, the reason for the lack of cleavage of the GlcUA-GlcNS6S linkage in the S-domain is less clear.…”

Section: Discussionmentioning

confidence: 99%

Deciphering Mode of Action of Heparanase Using Structurally Defined Oligosaccharides

Peterson

Liu

2012

Journal of Biological Chemistry

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Background: Heparanase is involved in the pathology of many diseases. Results: Heparanase cleaves heparan sulfate (HS) oligosaccharides in either consecutive or gapped cleavage mode. Conclusion: The susceptibility of glycosidic linkage bonds to heparanase degradation is sensitive to the nonreducing end saccharide structure of the cleavage site. Significance: The results will help us to understand the pathophysiological effects of HS that arise from heparanase activity.

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Section: Discussionmentioning

confidence: 99%

Deciphering Mode of Action of Heparanase Using Structurally Defined Oligosaccharides

Peterson

Liu

2012

Journal of Biological Chemistry

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“…Given the fact the modification of NDST-1 is exclusively toward the reducing end, our model suggests that the cluster of N-S domain should be longer if the N-sulfation is initiated at the nonreducing end. Indeed, structural analysis of the HS from various tissues indicated that the size of N-S domain is longer than those N-S domains identified in the middle of polysaccharide (28). NDST-1 contains both N-deacetylase and N-sulfotransferase domains.…”

Section: Discussionmentioning

confidence: 99%

The Dominating Role of N-Deacetylase/N-Sulfotransferase 1 in Forming Domain Structures in Heparan Sulfate

Sheng

Liu

et al. 2011

Journal of Biological Chemistry

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Heparan sulfate (HS) is a highly sulfated polysaccharide participated in essential physiological functions from regulating cell growth to blood coagulation. HS contains sulfated domains known as N-S domains and low sulfate domains known as N-Ac domains. The distribution of the domain structures is likely governed by the action of glucosaminyl N-deacetylase/N-sulfotransferase (NDST). Here, we sought to determine the substrate specificity of NDST using model substrates and recombinant NDST protein. We discovered that NDST-1 carries out the modification in a highly ordered fashion. The enzyme sulfates the substrate from the nonreducing end toward the reducing end consecutively, leading to the product with a cluster of N-sulfo glucosamine residues. Furthermore, a preexisting N-sulfo glucosamine residue prevents the action of NDST-1 at the residues immediately located at the nonreducing end, allowing the formation of an N-Ac domain. Our results provide the long sought evidence for understanding the formation of sulfated versus nonsulfated domains in the HS isolated from cells and tissues. The study demonstrates the regulating role of NDST-1 in mapping the sulfation patterns of HS.

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“…56,57 Briefly, GAGs were released using 0.5 M NaOH, followed by purification using weak anion exchange chromatography. Samples were then digested into disaccharides by heparin lyases I, II, and III from Flavobacterium heparinum (Ibex, Montreal, Canada) at 37°C.…”

Section: Hs Disaccharide Analysismentioning

confidence: 99%

WT1-Dependent Sulfatase Expression Maintains the Normal Glomerular Filtration Barrier

Schumacher

Schlötzer‐Schrehardt²,

Karumanchi

et al. 2011

Journal of the American Society of Nephrology

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Paracrine signaling between podocytes and glomerular endothelial cells through vascular endothelial growth factor A (VEGFA) maintains a functional glomerular filtration barrier. Heparan sulfate proteoglycans (HSPGs), located on the cell surface or in the extracellular matrix, bind signaling molecules such as VEGFA and affect their local concentrations, but whether modulation of these moieties promotes normal crosstalk between podocytes and endothelial cells is unknown. Here, we found that the transcription factor Wilms' Tumor 1 (WT1) modulates VEGFA and FGF2 signaling by increasing the expression of the 6-O-endosulfatases Sulf1 and Sulf2, which remodel the heparan sulfate 6-O-sulfation pattern in the extracellular matrix. Mice deficient in both Sulf1 and Sulf2 developed age-dependent proteinuria as a result of ultrastructural abnormalities in podocytes and endothelial cells, a phenotype similar to that observed in children with WT1 mutations and in Wt1 ϩ/Ϫ mice. These kidney defects associated with a decreased distribution of VEGFA in the glomerular basement membrane and on endothelial cells. Collectively, these data suggest that WT1-dependent sulfatase expression plays a critical role in maintaining the glomerular filtration barrier by modulating the bioavailability of growth factors, thereby promoting normal crosstalk between podocytes and endothelial cells.

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Extended N-Sulfated Domains Reside at the Nonreducing End of Heparan Sulfate Chains

Cited by 48 publications

References 48 publications

Deciphering Mode of Action of Heparanase Using Structurally Defined Oligosaccharides

Deciphering Mode of Action of Heparanase Using Structurally Defined Oligosaccharides

The Dominating Role of N-Deacetylase/N-Sulfotransferase 1 in Forming Domain Structures in Heparan Sulfate

WT1-Dependent Sulfatase Expression Maintains the Normal Glomerular Filtration Barrier

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