Heparinase I from Flavobacterium heparinum

Sasisekharan, Ram; Venkataraman, Ganesh; Godavarti, Ranga; Ernst, Steffen; Cooney, Charles L.; Langer, Robert

doi:10.1074/jbc.271.6.3124

Cited by 63 publications

(70 citation statements)

References 57 publications

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“…Other natural ligands, such as lipopolysaccharides, mucins, and glycosaminoglycans, present a heterogeneous display of potential receptor binding sites, even within the same molecule. [113,114] A casual visual comparison between the architecture of sTALL and a typical glycosaminoglycan will reveal very few similarities in either size, shape, or RE density. Despite their dramatic structural differences, both sTALL and glycosaminoglycans are involved in clustering cell surface receptors.…”

Section: Classes Of Multivalent Ligand Architecturesmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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Section: Classes Of Multivalent Ligand Architecturesmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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“…1,4,7 Biosynthesis of GAGs is a nontemplate-driven process and takes place in the Golgi compartment of eukaryotic cells in response to an external stimulus or at a particular stage of development. 8 While the importance of PGs and their potential as new therapeutic agents, targets, and disease markers are well recognized, 3,[9][10][11][12] sequence determination of GAGs remains a challenging task. Methods for GAG sequencing reported to date rely on a bottom-up approach which involves characterization of depolymerized fragments of GAGs that can be assembled like pieces of a puzzle into motifs or domains.…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Bikunin Glycosaminoglycan

et al. 2008

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The structure of an intact glycosaminoglycan (GAG) chain of the bikunin proteoglycan (PG) was analyzed using a combined top-down and bottom-up sequencing strategy. PGs are proteins with one or more linear, high-molecular weight, sulfated GAG polysaccharides O-linked to serine or threonine residues. GAGs are often responsible for the biological functions of PGs, and subtle variations in the GAG structure have pronounced physiological effects. Bikunin is a serine protease inhibitor found in human amniotic fluid, plasma, and urine. Bikunin is posttranslationally modified with a chondroitin sulfate (CS) chain, O-linked to a serine residue of the core protein.Recent studies have shown that the CS chain of bikunin plays an important role in the physiological and pathological functions of this PG. While no PG or GAG has yet been sequenced, bikunin, the least complex PG, offers a compelling target. Electrospray ionization Fourier transform-ion cyclotron resonance mass spectrometry (ESI FTICR-MS) permitted the identification of several major components in the GAG mixture having molecular masses in a range of 5505-7102 Da. This is the first report of a mass spectrum of an intact GAG component of a PG. FTICR-MS analysis of a size-uniform fraction of bikunin GAG mixture obtained by preparative polyacrylamide gel electrophoresis, allowed the determination of chain length and number of sulfo groups in the intact GAGs.

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“…Heparan sulfate-like glycosaminoglycans (HSGAGs), along with structural proteins, are key components of the cell surface-ECM interface. Whereas collagen-like proteins provide the necessary scaffold for cell attachment and tissue formation, the HSGAG complex polysaccharides fill the scaffold and act as a molecular sponge by specifically binding to and regulating the activities of numerous signaling molecules such as growth factors and cytokines (1,2). Important progress has been made in understanding the diverse roles of collagen (and related proteins) and enzymes (namely, collagenases) that degrade the proteinaceous component of the ECM in regulating tumor growth and metastasis (3,4).…”

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confidence: 99%

Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis

Liu

Shriver²,

Venkataraman³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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208

110

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Heparan sulfate glycosaminoglycans, present at the cell surface and in the extracellular matrix that surrounds cells, are important mediators of complex biological processes. Furthermore, it is now apparent that cells dynamically regulate the structure of their heparan sulfate ''coat'' to differentially regulate extracellular signals. In the present study, the importance of sequence information contained within tumor cell-surface heparan sulfate was investigated. Herein, we demonstrate that the heparan sulfate glycosaminoglycan coat present on tumor cells contains bioactive sequences that impinge on tumor-cell growth and metastasis. Importantly, we find that growth promoting as well as growth inhibiting sequences are contained within the polysaccharide coat. Furthermore, we find that the dynamic balance between these distinct polysaccharide populations regulates specific intracellular signal-transduction pathways. This study not only provides a framework for the development of polysaccharide-based anti-cancer molecules but also underscores the importance of understanding a cell's polysaccharide array in addition to its protein complement, to understand how genotype translates to phenotype in this postgenomic age.

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Heparinase I from Flavobacterium heparinum

Cited by 63 publications

References 57 publications

Synthetic Multivalent Ligands as Probes of Signal Transduction

Synthetic Multivalent Ligands as Probes of Signal Transduction

Structural Analysis of Bikunin Glycosaminoglycan

Tumor cell surface heparan sulfate as cryptic promoters or inhibitors of tumor growth and metastasis

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