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Jeffrey D Esko - One of the best experts on this subject based on the ideXlab platform.

  • demystifying Heparan Sulfate protein interactions
    Annual Review of Biochemistry, 2014
    Co-Authors: Ding Xu, Jeffrey D Esko
    Abstract:

    Numerous proteins, including cytokines and chemokines, enzymes and enzyme inhibitors, extracellular matrix proteins, and membrane receptors, bind heparin. Although they are traditionally classified as heparin-binding proteins, under normal physiological conditions these proteins actually interact with the Heparan Sulfate chains of one or more membrane or extracellular proteoglycans. Thus, they are more appropriately classified as Heparan Sulfate-binding proteins (HSBPs). This review provides an overview of the various modes of interaction between Heparan Sulfate and HSBPs, emphasizing biochemical and structural insights that improve our understanding of the many biological functions of Heparan Sulfate.

  • Demystifying Heparan Sulfate–Protein Interactions
    Annual Review of Biochemistry, 2014
    Co-Authors: Ding Xu, Jeffrey D Esko
    Abstract:

    Numerous proteins, including cytokines and chemokines, enzymes and enzyme inhibitors, extracellular matrix proteins, and membrane receptors, bind heparin. Although they are traditionally classified as heparin-binding proteins, under normal physiological conditions these proteins actually interact with the Heparan Sulfate chains of one or more membrane or extracellular proteoglycans. Thus, they are more appropriately classified as Heparan Sulfate–binding proteins (HSBPs). This review provides an overview of the various modes of interaction between Heparan Sulfate and HSBPs, emphasizing biochemical and structural insights that improve our understanding of the many biological functions of Heparan Sulfate.

  • Heparan Sulfate Regulates VEGF165- and VEGF121-mediated Vascular Hyperpermeability
    Journal of Biological Chemistry, 2010
    Co-Authors: Ding Xu, Mark M Fuster, Roger Lawrence, Jeffrey D Esko
    Abstract:

    Abstract VEGF was first described as vascular permeability factor, a potent inducer of vascular leakage. Genetic evidence indicates that VEGF-stimulated endothelial proliferation in vitro and angiogenesis in vivo depend on Heparan Sulfate, but a requirement for Heparan Sulfate in vascular hyperpermeability has not been explored. Here we show that altering endothelial cell Heparan Sulfate biosynthesis in vivo decreases hyperpermeability induced by both VEGF165 and VEGF121. Since VEGF121 does not bind Heparan Sulfate, the requirement for Heparan Sulfate suggested that it interacted with VEGF receptors rather than the ligand. By applying proximity ligation assays to primary brain endothelial cells, we show a direct interaction in situ between Heparan Sulfate and the VEGF receptor, VEGFR2. Furthermore, the number of Heparan Sulfate/VEGFR2 complexes increased in response to both VEGF165 and VEGF121. Genetic or heparin lyase-mediated alteration of endothelial Heparan Sulfate attenuated phosphorylation of VEGFR2 in response to VEGF165 and VEGF121, suggesting that the functional VEGF receptor complex contains Heparan Sulfate. Pharmacological blockade of Heparan Sulfate-protein interactions inhibited hyperpermeability in vivo, suggesting Heparan Sulfate as a potential target for treating hyperpermeability associated with ischemic disease.

  • surfen a small molecule antagonist of Heparan Sulfate
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Manuela Schuksz, Mark M Fuster, Jillian R Brown, Brett E Crawford, David Ditto, Roger Lawrence, Charles A Glass, Lianchun Wang, Jeffrey D Esko
    Abstract:

    In a search for small molecule antagonists of Heparan Sulfate, we examined the activity of bis-2-methyl-4-amino-quinolyl-6-carbamide, also known as surfen. Fluorescence-based titrations indicated that surfen bound to glycosaminoglycans, and the extent of binding increased according to charge density in the order heparin > dermatan Sulfate > Heparan Sulfate > chondroitin Sulfate. All charged groups in heparin (N-Sulfates, O-Sulfates, and carboxyl groups) contributed to binding, consistent with the idea that surfen interacted electrostatically. Surfen neutralized the anticoagulant activity of both unfractionated and low molecular weight heparins and inhibited enzymatic sulfation and degradation reactions in vitro. Addition of surfen to cultured cells blocked FGF2-binding and signaling that depended on cell surface Heparan Sulfate and prevented both FGF2- and VEGF165-mediated sprouting of endothelial cells in Matrigel. Surfen also blocked Heparan Sulfate-mediated cell adhesion to the Hep-II domain of fibronectin and prevented infection by HSV-1 that depended on glycoprotein D interaction with Heparan Sulfate. These findings demonstrate the feasibility of identifying small molecule antagonists of Heparan Sulfate and raise the possibility of developing pharmacological agents to treat disorders that involve glycosaminoglycan–protein interactions.

  • Heparan Sulfate proteoglycans and triglyceride-rich lipoprotein metabolism.
    Current opinion in lipidology, 2008
    Co-Authors: Joseph R. Bishop, Kristin I. Stanford, Jeffrey D Esko
    Abstract:

    PURPOSE OF REVIEW Clearance of triglyceride-rich lipoprotein remnants by the liver is a key step in preventing hypertriglyceridemia, an independent risk factor for cardiovascular disease. We review recent genetic evidence that Heparan Sulfate proteoglycans work in concert with the LDL receptor in the liver to facilitate binding and clearance of both triglyceride and cholesterol-rich lipoproteins from the circulation. RECENT FINDINGS Partial reduction of sulfation of liver Heparan Sulfate using the Cre-loxP system caused accumulation of hepatic and dietary triglyceride-rich lipoprotein particles due to delayed clearance. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol and triglyceride-rich particles compared with mice lacking only LDL receptors. These findings provide the first genetic evidence that hepatic Heparan Sulfate proteoglycans play a central role in the clearance of lipoproteins by the liver and work independently of LDL receptors. SUMMARY A role for hepatocyte Heparan Sulfate in lipoprotein metabolism has now been genetically established in mice. Given this finding, mild, but clinically relevant, hyperlipidemias in human patients may be a result of alterations in Heparan Sulfate structure or possible genetic polymorphisms in the relevant biosynthetic genes.

Robert J. Linhardt - One of the best experts on this subject based on the ideXlab platform.

  • Quantitative analysis of Heparan Sulfate using isotopically labeled calibrants.
    Communications biology, 2020
    Co-Authors: Zhangjie Wang, Robert J. Linhardt, Katelyn Arnold, Vijayakanth Pagadala, Hannah Myatt, Jian Liu
    Abstract:

    Heparan Sulfate is a Sulfated polysaccharide that displays essential physiological functions. Here, we report a LC-MS/MS-based method for quantitatively determining the individual disaccharide composition and total amount of Heparan Sulfate. Using eight 13C-labeled disaccharide calibrants and one 13C-labeled polysaccharide calibrant, we complete the analysis in one-pot process. The method is both sensitive and has the throughput to analyze Heparan Sulfate from mouse tissues and plasma. Wang et al. describe a strategy for quantitatively performing composition analysis of Heparan Sulfate using 13C-labeled disaccharides and polysaccharides that mimic the glycosaminoglycan chemical structure. They further show that these isotopically labelled small molecules can be used as internal standards for mass spectrometry analysis of Heparan Sulfate derived from mouse tissue and plasma.

  • chemoenzymatic synthesis of Heparan Sulfate and heparin
    Natural Product Reports, 2014
    Co-Authors: Robert J. Linhardt
    Abstract:

    Covering: up to May 2014 Heparan Sulfate is a polysaccharide that plays essential physiological functions in the animal kingdom. Heparin, a highly Sulfated form of Heparan Sulfate, is a widely prescribed anticoagulant drug worldwide. The Heparan Sulfate and heparin isolated from natural sources are highly heterogeneous mixtures differing in their polysaccharide chain lengths and sulfation patterns. The access to structurally defined Heparan Sulfate and heparin is critical to probe the contribution of specific Sulfated saccharide structures to the biological functions as well as for the development of the next generation of heparin-based anticoagulant drugs. The synthesis of Heparan Sulfate and heparin, using a purely chemical approach, has proven extremely difficult, especially for targets larger than octasaccharides having a high degree of site-specific sulfation. A new chemoenzymatic method has emerged as an effective alternative approach. This method uses recombinant Heparan Sulfate biosynthetic enzymes combined with unnatural uridine diphosphate-monosaccharide donors. Recent examples demonstrate the successful synthesis of ultra-low molecular weight heparin, low-molecular weight heparin and bioengineered heparin with unprecedented efficiency. The new method provides an opportunity to develop improved heparin-based therapeutics.

  • chemoenzymatic design of Heparan Sulfate oligosaccharides
    Journal of Biological Chemistry, 2010
    Co-Authors: Yongmei Xu, Miao Chen, Michel Weiwer, Xianxuan Zhou, Arlene S Bridges, Paul L Deangelis, Qisheng Zhang, Robert J. Linhardt
    Abstract:

    Abstract Heparan Sulfate is a Sulfated glycan that exhibits essential physiological functions. Interrogation of the specificity of Heparan Sulfate-mediated activities demands a library of structurally defined oligosaccharides. Chemical synthesis of large Heparan Sulfate oligosaccharides remains challenging. We report the synthesis of oligosaccharides with different sulfation patterns and sizes from a disaccharide building block using glycosyltransferases, Heparan Sulfate C5-epimerase, and sulfotransferases. This method offers a generic approach to prepare Heparan Sulfate oligosaccharides possessing predictable structures.

  • Physiological, Pathophysiological and Therapeutic Roles of Heparin and Heparan Sulfate
    Carbohydrate Chemistry Biology and Medical Applications, 2008
    Co-Authors: Saravanababu Murugesan, Robert J. Linhardt
    Abstract:

    Publisher Summary Heparin and Heparan Sulfate belong to the glycosaminoglycan (GAG) family of carbohydrates. They are linear acidic complex polysaccharides found on the cell surface and in the extracellular matrix. Heparin and Heparan Sulfate GAGs are biosynthesized as proteoglycans (PGs) with multiple GAG chains linked to a variety of core proteins. Heparin PGs are found exclusively in the granules of subsets of mast cells, whereas Heparan Sulfate PGs have a much greater distribution in the body, being associated with stromal matrices, basement membranes, and almost all cell surfaces. Heparin and Heparan Sulfate PGs interact with cell surface binding proteins and are internalized by receptor-mediated endocytosis through their GAG chains. Heparin and Heparan Sulfate are the most intensively studied GAGs as a result of their anticoagulant properties. However, it has become obvious that heparin and Heparan Sulfate not only have anticoagulant activities but also exhibit a number of diverse biological functions including ones regulating cell growth and differentiation, inflammatory processes, host defense and viral infection mechanisms, cell–cell and cell–matrix interactions, lipid transport, and clearance/metabolism. These functions result from the direct interactions between heparin and Heparan Sulfate and heparin-binding proteins.

  • Enzymatic Redesigning of Biologically Active Heparan Sulfate
    Journal of Biological Chemistry, 2005
    Co-Authors: Jinghua Chen, Miao Chen, Lijuan Zhang, Fikri Y. Avci, Eva Muñoz, Lynda M. Mcdowell, Lars C. Pedersen, Robert J. Linhardt
    Abstract:

    Heparan Sulfate carries a wide range of biological activities, regulating blood coagulation, cell differentiation, and inflammatory responses. The sulfation patterns of the polysaccharide are essential for the biological activities. In this study, we report an enzymatic method for the sulfation of multimilligram amounts of Heparan Sulfate with specific functions using immobilized sulfotransferases combined with a 3'-phosphoadenosine 5'-phosphoSulfate regeneration system. By selecting appropriate enzymatic modification steps, an inactive precursor has been converted to the Heparan Sulfate having three distinct biological activities, associated with binding to antithrombin, fibroblast growth factor-2, and herpes simplex virus envelope glycoprotein D. Because the recombinant sulfotransferases are expressed in bacteria, and the method uses a low cost sulfo donor, it can be readily utilized to synthesize large quantities of anticoagulant heparin drug or other biologically active Heparan Sulfates.

Ralph D. Sanderson - One of the best experts on this subject based on the ideXlab platform.

  • Heparan Sulfate Chains of Syndecan-1 Regulate Ectodomain Shedding
    Journal of Biological Chemistry, 2012
    Co-Authors: Vishnu C. Ramani, Pamela S. Pruett, Camilla A. Thompson, Lawrence D. Delucas, Ralph D. Sanderson
    Abstract:

    Abstract Matrix metalloproteinases release intact syndecan-1 ectodomains from the cell surface giving rise to a soluble, shed form of the proteoglycan. Although it is known that shed syndecan-1 controls diverse pathophysiological responses in cancer, wound healing, inflammation, infection, and immunity, the mechanisms regulating shedding remain unclear. We have discovered that the Heparan Sulfate chains present on syndecan core proteins suppress shedding of the proteoglycan. Syndecan shedding is dramatically enhanced when the Heparan Sulfate chains are enzymatically degraded or absent from the core protein. Exogenous Heparan Sulfate or heparin does not inhibit shedding, indicating that Heparan Sulfate must be attached to the core protein to suppress shedding. Regulation of shedding by Heparan Sulfate occurs in multiple cell types, for both syndecan-1 and syndecan-4 and in murine and human syndecans. Mechanistically, the loss of Heparan Sulfate enhances the susceptibility of the core protein to proteolytic cleavage by matrix metalloproteinases. Enhanced shedding of syndecan-1 following loss of Heparan Sulfate is accompanied by a dramatic increase in core protein synthesis. This suggests that in response to an increase in the rate of shedding, cells attempt to maintain a significant level of syndecan-1 on the cell surface. Together these data indicate that the amount of Heparan Sulfate present on syndecan core proteins regulates both the rate of syndecan shedding and core protein synthesis. These findings assign new functions to Heparan Sulfate chains, thereby broadening our understanding of their physiological importance and implying that therapeutic inhibition of Heparan Sulfate degradation could impact the progression of some diseases.

  • Heparan Sulfate proteoglycans in invasion and metastasis
    Seminars in cell & developmental biology, 2001
    Co-Authors: Ralph D. Sanderson
    Abstract:

    Because Heparan Sulfate proteoglycans mediate cell adhesion and control the activities of numerous growth and motility factors, they play a critical role in regulating the metastatic behavior of tumor cells. Due to their utilitarian nature, Heparan Sulfate proteoglycans may at times act as inhibitors of cell invasion and at other times as promoters of cell invasion, with their function being determined by their location (cell surface or extracellular matrix), the heparin-binding molecules they associate with, the presence of modifying enzymes (proteases, Heparanases) and the precise structural characteristics of the proteoglycan. Also, the tissue type and pathophysiological state of the tumor influence proteogylcan function. This review summarizes our current knowledge of the role Heparan Sulfate proteoglycans play in regulating tumor cell metastasis, proposes mechanisms of how these molecules function and examines the potential for discovery of new therapeutic approaches designed to block metastatic cancer.

  • MULTIPLE Heparan Sulfate CHAINS ARE REQUIRED FOR OPTIMAL SYNDECAN-1 FUNCTION
    The Journal of biological chemistry, 1998
    Co-Authors: J. Kevin Langford, Michelle J. Stanley, Dianjun Cao, Ralph D. Sanderson
    Abstract:

    Abstract Syndecans have three highly conserved sites available for Heparan Sulfate attachment. To determine if all three sites are required for normal function, a series of mutated syndecans having two, one, or no Heparan Sulfate chains were expressed in ARH-77 cells. Previously, we demonstrated that expression of wild-type syndecan-1 on these myeloma cells mediates cell-matrix and cell-cell adhesion and inhibits cell invasion into collagen gels. Here we show that to optimally mediate each of these activities, all three sites of Heparan Sulfate attachment are required. Generally, an increasing loss of syndecan-1 function occurs as the number of Heparan Sulfate attachment sites decreases. This loss of function is not the result of a decrease in either the total amount of cell surface Heparan Sulfate or syndecan-1 core protein. In regard to cell invasion, cells expressing syndecan-1 bearing a single Heparan Sulfate attachment site exhibit a hierarchy of function based upon the position of the site within the core protein; the presence of an available attachment site at serine 47 confers the greatest level of activity, while serine 37 contributes little to syndecan-1 function. However, when all three Heparan Sulfate chains are present, significantly greater biological activity is observed than is predicted by the sum of the activities occurring when the chains act individually. This synergy provides a functional basis for the evolutionary conservation of the three Heparan Sulfate attachment sites on syndecans and supports the idea that molecular heterogeneity, which is characteristic of proteoglycans, contributes to their functional diversity.

Suzanne C. Thorp - One of the best experts on this subject based on the ideXlab platform.

  • cell surface Heparan Sulfate and its roles in assisting viral infections
    Medicinal Research Reviews, 2002
    Co-Authors: Suzanne C. Thorp
    Abstract:

    Heparan Sulfate, a highly Sulfated polysaccharide, is present on the surface of mammalian cells and in the extracellular matrix in large quantities. The Sulfated monosaccharide sequences within Heparan Sulfate determine the protein binding specificity and regulate biological functions. Numerous viruses and parasites utilize cell surface Heparan Sulfate as receptors to infect target cells. Due to the structural complexity of Heparan Sulfate, it was considered a nonspecific cell surface receptor by interacting with the positive motifs of viral proteins. However, recent studies reveal that Heparan Sulfate plays multiple roles in assisting viral infection, and the activities in promoting viral infections require unique monosaccharide sequences, suggesting that Heparan Sulfate could serve as a specific receptor for viral infection. The currently available techniques for the structural analysis of Heparan Sulfate provide essential information about the specific roles of Heparan Sulfate in assisting viral infections. The knowledge accumulated in this fast growing field will permit us to have a better understanding of the mechanism of viral infection and will lead to the development of new antiviral agents. © 2001 John Wiley & Sons, Inc. Med Res Rev, 22, No. 1, 1–25, 2002

  • Cell surface Heparan Sulfate and its roles in assisting viral infections.
    Medicinal research reviews, 2001
    Co-Authors: Jian Liu, Suzanne C. Thorp
    Abstract:

    Heparan Sulfate, a highly Sulfated polysaccharide, is present on the surface of mammalian cells and in the extracellular matrix in large quantities. The Sulfated monosaccharide sequences within Heparan Sulfate determine the protein binding specificity and regulate biological functions. Numerous viruses and parasites utilize cell surface Heparan Sulfate as receptors to infect target cells. Due to the structural complexity of Heparan Sulfate, it was considered a nonspecific cell surface receptor by interacting with the positive motifs of viral proteins. However, recent studies reveal that Heparan Sulfate plays multiple roles in assisting viral infection, and the activities in promoting viral infections require unique monosaccharide sequences, suggesting that Heparan Sulfate could serve as a specific receptor for viral infection. The currently available techniques for the structural analysis of Heparan Sulfate provide essential information about the specific roles of Heparan Sulfate in assisting viral infections. The knowledge accumulated in this fast growing field will permit us to have a better understanding of the mechanism of viral infection and will lead to the development of new antiviral agents.

Branka Horvat - One of the best experts on this subject based on the ideXlab platform.

  • Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
    Mbio, 2015
    Co-Authors: Cyrille Mathieu, Kévin P. Dhondt, Marie Châlons, Stéphane Mély, Hervé Raoul, François-loïc Cosset, Denis Gerlier, Romain R Vives, Didier Negre, Branka Horvat
    Abstract:

    ABSTRACT Nipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genus Henipavirus . They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as Heparan Sulfate for both Nipah virus and Hendra virus. Cells devoid of Heparan Sulfate were not able to mediate henipavirus trans -infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound Heparan Sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the Heparan Sulfate and to block cell-mediated trans -infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cells in vitro . Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal Heparan Sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections. IMPORTANCE The Henipavirus genus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified Heparan Sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with Heparan Sulfate and to block cell-mediated trans -infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cells in vitro . Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of Heparan Sulfate in henipavirus infection and open novel perspectives for the development of Heparan Sulfate-targeting therapeutic approaches for these emerging infections.

  • Heparan Sulfate-dependent enhancement of henipavirus infection.
    mBio, 2015
    Co-Authors: Cyrille Mathieu, Kévin P. Dhondt, Marie Châlons, Stéphane Mély, Hervé Raoul, François-loïc Cosset, Denis Gerlier, Romain R Vives, Didier Negre, Branka Horvat
    Abstract:

    Nipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genus Henipavirus. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as Heparan Sulfate for both Nipah virus and Hendra virus. Cells devoid of Heparan Sulfate were not able to mediate henipavirus trans-infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound Heparan Sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the Heparan Sulfate and to block cell-mediated trans-infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cells in vitro. Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal Heparan Sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections. The Henipavirus genus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified Heparan Sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with Heparan Sulfate and to block cell-mediated trans-infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cells in vitro. Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of Heparan Sulfate in henipavirus infection and open novel perspectives for the development of Heparan Sulfate-targeting therapeutic approaches for these emerging infections.