Glycobiology and Extracellular Matrices
Fractionation of sulfated galactan from the red alga Botryocladia occidentalis separates its anticoagulant and anti-SARS-CoV-2 properties
Sulfation pattern and molecular weight (MW) play a key role in the biological actions of sulfated glycans. Besides anticoagulant effects, certain sulfated glycans can also exhibit anti-SARS-CoV-2 properties. To develop a more selective antiviral carbohydrate, an efficient strategy to separate these two actions is required. In this work, low MW fractions derived from the red alga Botryocladia occidentalis sulfated galactan (BoSG) were generated, structurally characterized, and tested for activity against SARS-CoV-2 and blood coagulation.Structural and kinetic analyses of holothurian sulfated glycans suggest potential treatment for SARS-CoV-2 infection
Certain sulfated glycans, including those from marine sources, can show potential effects against SARS-CoV-2. Here, a new fucosylated chondroitin sulfate (FucCS) from the sea cucumber Pentacta pygmaea (PpFucCS) (MW ∼10–60 kDa) was isolated and structurally characterized by NMR. PpFucCS is composed of {→3)-β-GalNAcX-(1→4)-β-GlcA-[(3→1)Y]-(1→}, where X = 4S (80%), 6S (10%) or nonsulfated (10%), Y = α-Fuc2,4S (40%), α-Fuc2,4S-(1→4)-α-Fuc (30%), or α-Fuc4S (30%), and S = SO3−. The anti-SARS-CoV-2 activity of PpFucCS and those of the FucCS and sulfated fucan isolated from Isostichopus badionotus (IbFucCS and IbSF) were compared with that of heparin.Ischemic stroke disrupts the endothelial glycocalyx through activation of proHPSE via acrolein exposure
Infiltration of peripheral immune cells after blood-brain barrier dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells, functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans, a component of the endothelial glycocalyx, were studied in the context of ischemic stroke using a photochemically induced thrombosis mouse model.Dimerization interface of osteoprotegerin revealed by hydrogen–deuterium exchange mass spectrometry
Previous structural studies of osteoprotegerin (OPG), a crucial negative regulator of bone remodeling and osteoclastogenesis, were mostly limited to the N-terminal ligand-binding domains. It is now known that the three C-terminal domains of OPG also play essential roles in its function by mediating OPG dimerization, OPG–heparan sulfate (HS) interactions, and formation of the OPG–HS–receptor activator of nuclear factor κB ligand (RANKL) ternary complex. Employing hydrogen–deuterium exchange MS methods, here we investigated the structure of full-length OPG in complex with HS or RANKL in solution.Decline in arylsulfatase B expression increases EGFR expression by inhibiting the protein-tyrosine phosphatase SHP2 and activating JNK in prostate cells
Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to be up-regulated when arylsulfatase B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously been reported to inhibit the activity of the ubiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism by which decline in ARSB leads to decline in SHP2 activity is unclear.Heparan Sulfate Domains Required for Fibroblast Growth Factor 1 and 2 Signaling through Fibroblast Growth Factor Receptor 1c
A small library of well defined heparan sulfate (HS) polysaccharides was chemoenzymatically synthesized and used for a detailed structure-activity study of fibroblast growth factor (FGF) 1 and FGF2 signaling through FGF receptor (FGFR) 1c. The HS polysaccharide tested contained both undersulfated (NA) domains and highly sulfated (NS) domains as well as very well defined non-reducing termini. This study examines differences in the HS selectivity of the positive canyons of the FGF12-FGFR1c2 and FGF22-FGFR1c2 HS binding sites of the symmetric FGF2-FGFR2-HS2 signal transduction complex.The Responses of Hyperglycemic Dividing Mesangial Cells to Heparin Are Mediated by the Non-reducing Terminal Trisaccharide
Background: Heparin prevents intracellular hyaluronan synthesis and subsequent autophagy in hyperglycemic dividing mesangial cells.Results: The non-reducing terminal trisaccharide of heparin is sufficient for this response.Conclusion: This heparin trisaccharide motif is exposed by the mammalian heparanase and is recognized by a receptor on dividing cells.Significance: The trisaccharide does not have the anti-coagulant properties of heparin.2-O-Sulfated Domains in Syndecan-1 Heparan Sulfate Inhibit Neutrophil Cathelicidin and Promote Staphylococcus aureus Corneal Infection
Background: Syndecan-1 promotes bacterial infections, but how this is accomplished remains unclear.Results: Syndecan-1 and 2-O-sulfated heparan compounds specifically enhanced S. aureus corneal virulence and inhibited bacterial killing by CRAMP secreted from degranulated neutrophils.Conclusion: Specific structural motifs in syndecan-1 HS promote S. aureus corneal infection by inhibiting neutrophil CRAMP.Significance: This study uncovers a new pathogenic role for syndecan-1 in bacterial infection.High Structural Resolution Hydroxyl Radical Protein Footprinting Reveals an Extended Robo1-Heparin Binding Interface
Background: The molecular basis of full-length heparin activation of Slit-Robo is poorly understood, despite its importance in nervous system development.Results: Two separate binding sites of Robo1-full length heparin interaction were identified.Conclusion: A model for heparin/heparan sulfate binding and activation of the Slit-Robo complex is proposed.Significance: A previously unidentified Robo1 low affinity binding site for heparin may be required for signal transduction.Heavy Chain Transfer by Tumor Necrosis Factor-stimulated Gene 6 to the Bikunin Proteoglycan
Background: The glycosaminoglycan of bikunin is less than 40 monosaccharides in length, but it can reversibly accept two heavy chains (HCs).Results: TSG-6 can reversibly transfer a single HC to the glycosaminoglycan of bikunin.Conclusion: The core protein, or sulfated glycosaminoglycan, of bikunin promotes reversible HC transfer to its relatively short CS chain.Significance: The intracellular assembly of inter-α-inhibitor is likely independent of transesterification by TSG-6.
