scholarly journals Faculty Opinions recommendation of Structural Features of Heparan Sulfate from Multiple Osteochondromas and Chondrosarcomas.

2019 ◽  
Author(s):  
Judith Bovee ◽  
Ieva Palubeckaite
Keyword(s):  
Heparan Sulfate ◽  
Structural Features ◽  
Multiple Osteochondromas

scholarly journals Structural Features of Heparan Sulfate from Multiple Osteochondromas and Chondrosarcomas

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3277 ◽  
Author(s):  
Noemi Veraldi ◽  
Alessandro Parra ◽  
Elena Urso ◽  
Cesare Cosentino ◽  
Manuela Locatelli ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Bone Growth ◽  
Structural Features ◽  
Signaling Networks ◽  
Phenotypic Differences ◽  
Multiple Osteochondromas ◽  
Structural Differences ◽  
Set Up ◽  
First Time ◽  
Cartilaginous Tumors

Multiple osteochondromas (MO) is a hereditary disorder associated with benign cartilaginous tumors, known to be characterized by absence or highly reduced amount of heparan sulfate (HS) in the extracellular matrix of growth plate cartilage, which alters proper signaling networks leading to improper bone growth. Although recent studies demonstrated accumulation of HS in the cytoplasm of MO chondrocytes, nothing is known on the structural alterations which prevent HS from undergoing its physiologic pathway. In this work, osteochondroma (OC), peripheral chondrosarcoma, and healthy cartilaginous human samples were processed following a procedure previously set up to structurally characterize and compare HS from pathologic and physiologic conditions, and to examine the phenotypic differences that arise in the presence of either exostosin 1 or 2 (EXT1 or EXT2) mutations. Our data suggest that HS chains from OCs are prevalently below 10 kDa and slightly more sulfated than healthy ones, whereas HS chains from peripheral chondrosarcomas (PCSs) are mostly higher than 10 kDa and remarkably more sulfated than all the other samples. Although deeper investigation is still necessary, the approach here applied pointed out, for the first time, structural differences among OC, PCS, and healthy HS chains extracted from human cartilaginous excisions, and could help in understanding how the structural features of HS are modulated in the presence of pathological situations also involving different tissues.

Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity

2008 ◽  
Vol 294 (6) ◽  
pp. C1387-C1397 ◽  
Author(s):  
Shaukat A. Khan ◽  
Matthew S. Nelson ◽  
Chendong Pan ◽  
Patrick M. Gaffney ◽  
Pankaj Gupta
Keyword(s):  
Heparan Sulfate ◽  
Bone Morphogenetic Proteins ◽  
Bone Development ◽  
Structural Features ◽  
Bmp Signaling ◽  
Hurler Syndrome ◽  
Multipotent Stem Cells ◽  
Pharmacological Agents ◽  
Chemically Modified ◽  
Morphogenetic Protein

Bone morphogenetic proteins (BMPs) and their endogenous antagonists are important for brain and bone development and tumor initiation and progression. Heparan sulfate (HS) proteoglycans (HSPG) modulate the activities of BMPs and their antagonists. How glycosaminoglycans (GAGs) influence BMP activity in various malignancies and in inherited abnormalities of GAG metabolism, and the structural features of GAGs essential for modulation of BMP signaling, remain incompletely defined. We examined whether chemically modified soluble heparins, the endogenous HS in malignant cells and the HS accumulated in Hurler syndrome cells influence BMP-4 signaling and activity. We show that both exogenous (soluble) and endogenous GAGs modulate BMP-4 signaling and activity, and that this effect is dependent on specific sulfate residues of GAGs. Our studies suggest that endogenous sulfated GAGs promote the proliferation and impair differentiation of malignant human cells, providing the rationale for investigating whether pharmacological agents that inhibit GAG synthesis or function might reverse this effect. Our demonstration of impairment of BMP-4 signaling by GAGs in multipotent stem cells in human Hurler syndrome identifies a mechanism that might contribute to the progressive neurological and skeletal abnormalities in Hurler syndrome and related mucopolysaccharidoses.

scholarly journals Elucidation of the Structural Features of Heparan Sulfate Important for Interaction with the Hep-2 Domain of Fibronectin

2000 ◽  
Vol 275 (7) ◽  
pp. 4599-4606 ◽  
Author(s):  
Malcolm Lyon ◽  
Graham Rushton ◽  
Janet A. Askari ◽  
Martin J. Humphries ◽  
John T. Gallagher
Keyword(s):  
Heparan Sulfate ◽  
Structural Features

scholarly journals Matrix-associated heparan sulfate proteoglycan: core protein-specific monoclonal antibodies decorate the pericellular matrix of connective tissue cells and the stromal side of basement membranes.

1989 ◽  
Vol 109 (6) ◽  
pp. 3199-3211 ◽  
Author(s):  
A Heremans ◽  
B van der Schueren ◽  
B de Cock ◽  
M Paulsson ◽  
J J Cassiman ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Monoclonal Antibodies ◽  
Epithelial Cell ◽  
Heparan Sulfate ◽  
Core Protein ◽  
Structural Features ◽  
Heparan Sulfate Proteoglycan ◽  
Basement Membranes ◽  
Lung Fibroblasts ◽  
Sulfate Proteoglycan

Cultured human lung fibroblasts produce a large, nonhydrophobic heparan sulfate proteoglycan that accumulates in the extracellular matrix of the monolayer (Heremans, A., J. J. Cassiman, H. Van den Berghe, and G. David. 1988. J. Biol. Chem. 263: 4731-4739). A panel of four monoclonal antibodies, specific for four distinct epitopes on the 400-kD core protein of this extracellular matrix heparan sulfate proteoglycan, detects similar proteoglycans in human epithelial cell cultures. Immunohistochemistry of human tissues with the monoclonal antibodies reveals that these proteoglycans are concentrated at cell-matrix interfaces. Immunogold labeling of ultracryosections of human skin indicates that the proteoglycan epitopes are nonhomogeneously distributed over the width of the basement membrane. Immunochemical investigations and amino acid sequence analysis indicate that the proteoglycan from the fibroblast matrix shares several structural features with the large, low density heparan sulfate proteoglycan isolated from the Engelbreth-Holm-Swarm sarcoma. Thus, both epithelial cell sheets and individual mesenchymal cells accumulate a large heparan sulfate proteoglycan(s) at the interface with the interstitial matrix, where the proteoglycan may adopt a specific topological orientation with respect to this matrix.

Identification of an MIP-1α–binding heparan sulfate oligosaccharide that supports long-term in vitro maintenance of human LTC-ICs

Blood ◽  
2003 ◽  
Vol 101 (6) ◽  
pp. 2243-2245 ◽  
Author(s):  
Sally E. Stringer ◽  
Matthew S. Nelson ◽  
Pankaj Gupta
Keyword(s):  
Protein Binding ◽  
Heparan Sulfate ◽  
Size Structure ◽  
Structural Features ◽  
Minimum Size ◽  
Binding Ability ◽  
Inflammatory Protein ◽  
Wide Range

We previously showed that heparan sulfate (HS) is required for in vitro cytokine + chemokine-mediated maintenance of primitive human hematopoietic progenitors. However, HS preparations are mixtures of polysaccharide chains of varying size, structure, and protein-binding abilities. Therefore, we examined whether the long-term culture-initiating cells (LTC-IC) supportive capability of HS is attributable to an oligosaccharide of defined length and protein-binding ability. Oligosaccharides of a wide range of sizes were prepared, and their capability to support human marrow LTC-IC maintenance in the presence of low-dose cytokines and a single chemokine, macrophage inflammatory protein-1α (MIP-1α), was examined. LTC-IC supportive capability of HS oligosaccharides correlated directly with size and MIP-1α binding ability. A specific MIP-1α-binding HS oligosaccharide preparation of Mr 10 kDa that optimally supported LTC-IC maintenance was identified. This oligosaccharide had the structure required for MIP-1α binding, which we have recently described. The present study defines the minimum size and structural features of LTC-IC supportive HS.

scholarly journals Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate

2020 ◽  
Author(s):  
Vaibhav Tiwari ◽  
Ritesh Tandon ◽  
Nehru Viji Sankaranarayanan ◽  
Jacob C. Beer ◽  
Ellen K. Kohlmeir ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Cell Fusion ◽  
Small Molecule ◽  
Structural Features ◽  
Wild Type ◽  
Spike Glycoprotein ◽  
Preferential Recognition ◽  
Synthetic Small Molecule

AbstractThe COVID-19 pandemic caused by SARS-CoV-2 is in immediate need of an effective antidote. Although the Spike glycoprotein (SgP) of SARS-CoV-2 has been shown to bind to heparins, the structural features of this interaction, the role of a plausible heparan sulfate proteoglycan (HSPG) receptor, and the antagonism of this pathway through small molecules remain unaddressed. Using an in vitro cellular assay, we demonstrate HSPGs modified by the 3-O-sulfotransferase isoform-3, but not isoform-5, preferentially increased SgP-mediated cell-to-cell fusion in comparison to control, unmodified, wild-type HSPGs. Computational studies support preferential recognition of the receptor-binding domain of SgP by 3-O-sulfated HS sequences. Competition with either fondaparinux, a 3-O-sulfated HS-binding oligopeptide, or a synthetic, non-sugar small molecule, blocked SgP-mediated cell-to-cell fusion. Finally, the synthetic, sulfated molecule inhibited fusion of GFP-tagged pseudo SARS-CoV-2 with human 293T cells with sub-micromolar potency. Overall, overexpression of 3-O-sulfated HSPGs contribute to fusion of SARS-CoV-2, which could be effectively antagonized by a synthetic, small molecule.

scholarly journals A unique heparan sulfate in the nuclei of hepatocytes: structural changes with the growth state of the cells.

1986 ◽  
Vol 102 (2) ◽  
pp. 587-599 ◽  
Author(s):  
N S Fedarko ◽  
H E Conrad
Keyword(s):  
Heparan Sulfate ◽  
Nuclear Membrane ◽  
Structural Changes ◽  
Gel Filtration ◽  
Deae Cellulose ◽  
Structural Features ◽  
The Other ◽  
Growth State ◽  
Before And After ◽  
Heparan Sulfates

Growing and confluent cultures of a rat hepatocyte cell line were labeled with 35SO4(2-) and the heparan sulfate in the culture medium, the pericellular matrix, the nucleus, the nuclear outer membrane, and the remaining cytoplasmic pool was purified by DEAE-cellulose chromatography. The heparan sulfate in all pools from the confluent cells was bound more strongly on the DEAE-cellulose column than the corresponding pools from the growing cells. Gel filtration of each pool before and after beta-elimination showed that the heparan sulfate from the nuclear and nuclear membrane pools was composed of primarily free chains, whereas the heparan sulfate in all of the other pools was a mixture of proteoglycans and free chains. The heparan sulfate in each pool was cleaved with nitrous acid to obtain mixtures of di- and tetrasaccharides. Analysis of these mixtures showed that the structural features of the heparan sulfates in each pool were different and were altered significantly when the growing cells became confluent. The nuclear-plus-nuclear membrane pools represented 6.5% and 5.4% of the total cell-associated heparan sulfate in the growing cells and the confluent cells, respectively. The structural features of the heparan sulfate in the two nuclear pools were very similar to each other, but were markedly different from those of the heparan sulfate from the other pools or from any previously described heparan sulfate or heparin. The most unusual aspect of these structures was the high content of beta-D-glucuronosyl(2-SO4)----D-glucosamine-N,O-(SO4)2 disaccharide units in these sequences. The mode of biosynthesis and delivery of these unusual sequences to the nucleus and the potential significance of these observations are discussed.

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