Controversial glycosaminoglycan conformations

Casu, Benito; Choay, J; Ferro, Dino R.; Gatti, Giuseppe; Jacquinet, Jean‐Claude; Petitou, Maurice; Provasoli, Augusto; Ragazzi, Massimo; Sînaÿ, Pierre; Torri, Giangiacomo

doi:10.1038/322215b0

Cited by 85 publications

(50 citation statements)

References 8 publications

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“…The conformationalb ehaviour of idose rings andd erivatives thereof has been am atter of investigation for years. [22,[42][43][44][45] It is well known that for l-idopyranoses, the theoretically more favourable 1 C 4 chair displays three axially oriented hydroxyl groups,w ith the correspondings teric consequences. The alternative 4 C 1 chair places the bulky hydroxymethyl group at the axial orientation,w ith the corresponding collapse.…”

Section: Methodsmentioning

confidence: 99%

Conformational Plasticity in Glycomimetics: Fluorocarbamethyl‐L‐idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings

Unione

Díaz

et al. 2015

Chemistry A European J

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Sugar function, structure and dynamics are intricately correlated. Ring flexibility is intrinsically related to biological activity; actually plasticity in L-iduronic rings modulates their interactions with biological receptors. However, the access to the experimental values of the energy barriers and free-energy difference for conformer interconversion in water solution has been elusive. Here, a new generation of fluorine-containing glycomimetics is presented. We have applied a combination of organic synthesis, NMR spectroscopy and computational methods to investigate the conformational behaviour of idose- and glucose-like rings. We have used low-temperature NMR spectroscopic experiments to slow down the conformational exchange of the idose-like rings. Under these conditions, the exchange rate becomes slow in the (19) F NMR spectroscopic chemical shift timescale and allows shedding light on the thermodynamic and kinetic features of the equilibrium. Despite the minimal structural differences between these compounds, a remarkable difference in their dynamic behaviour indeed occurs. The importance of introducing fluorine atoms in these sugars mimics is also highlighted. Only the use of (19) F NMR spectroscopic experiments has permitted the unveiling of key features of the conformational equilibrium that would have otherwise remained unobserved.

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Section: Methodsmentioning

confidence: 99%

Conformational Plasticity in Glycomimetics: Fluorocarbamethyl‐L‐idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings

Unione

Díaz

et al. 2015

Chemistry A European J

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“…The topology and geometry of a HSGAG structure is governed by the backbone torsion angles, which include both the intermonosaccharide glycosidic torsion angles and the pyranose ring torsion angles. Moreover, the pyranose ring of the ␣-iduronic acid can potentially adopt many conformations, including 4 C 1 , 1 C 4 chair, and the 2 S 0 skew boat forms (16)(17)(18)(19). Although it has been postulated that conformational flexibility of the iduronate ring enhances the specificity of HSGAG oligosaccharides binding to proteins, it is unclear how this and the ionic charges together translate to the required molecular specificity of HSGAG oligosaccharide-protein interactions.…”

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confidence: 99%

Structural specificity of heparin binding in the fibroblast growth factor family of proteins

Raman

Venkataraman²,

Ernst³

et al. 2003

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

148

125

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Heparin and heparan sulfate glycosaminoglycans (HSGAGs) mediate a wide variety of complex biological processes by specifically binding proteins and modulating their biological activity. One of the best studied model systems for protein-HSGAG interactions is the fibroblast growth factor (FGF) family of molecules, and recent observations have demonstrated that the specificity of a given FGF ligand binding to its cognate receptor (FGFR) is mediated by distinct tissuespecific HSGAG sequences. Although it has been known that sulfate and carboxylate groups in the HSGAG chain play a key role by interacting with basic residues on the proteins, there is little understanding of how these ionic interactions provide the necessary specificity for protein binding. In this study, using all of the available crystal structures of different FGFs and FGF-HSGAG complexes, we show that in addition to the ionic interactions, optimal van der Waals contact between the HSGAG oligosaccharide and the protein is also very important in influencing the specificity of FGF-HSGAG interactions. Although the overall helical structure is maintained in the FGF-bound HSGAG compared with unbound HSGAG, we observe distinct changes in the backbone torsion angles of the oligosaccharide chain induced upon protein binding. These changes result in local deviations in the helical axis that provide optimal ionic and van der Waals contact with the protein. A specific conformation and topological arrangement of the HSGAG-binding loops of FGF, on the other hand, impose structural constraints that induce the local deviations in the HSGAG structure, thereby enabling maximum contact between HSGAG and the protein.R ecent advances in developmental biology, cancer biology, and other fields have resulted in a dramatic increase in the number of known important roles for the extracellular complex polysaccharides heparin and heparan sulfate glycosaminoglycans (HSGAGs) (1-7). An emerging paradigm in this field is that unique HSGAG sequences specifically bind to a wide range of proteins (2, 5, 6), including morphogens (1, 7), growth factors (8-10), and enzymes (5, 11), and influence the physiological state of cells and tissues. Hence it is important to understand how sequence-specific HSGAG-protein interactions impinge on the biological functions of these important signaling molecules.HSGAGs are complex acidic polysaccharides that are characterized by a disaccharide repeat unit of ␣-D-glucosamine (1 3 4) linked to uronic (␣-L-iduronic͞␤-D-glucuronic) acid. Structural heterogeneity within the HSGAG polysaccharide arises from the number of disaccharide repeat units present, as well as four potential sites for chemical modification in the form of acetylation or sulfation. The sites of sulfation include the 2-O position of the uronic acid and the N, 3-O, and 6-O positions of the glucosamine, making HSGAG one of the most acidic biopolymers. Further, the N position of the glucosamine can also be acetylated. Similar to DNA and fibrous proteins like collagen, HSGAGs adopt a helica...

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“…This, along with the lack of proofreading activity of the modifying enzymes, the presence of tissue-dependent isozymes with different specificities (29), and the presence of post-biosynthetic chain modifying enzymes such as the 6-endosulfatases (30), leads to the high polydispersity and diverse sulfation patterns of HS. The anionic nature of HS coupled with its heterogeneity and its flexible conformation conferred by IdoA residues enables it to accommodate binding requirements for a large array of protein ligands (31). Heparin, a polysaccharide restricted to mast cells, is modified in the same way as NS domains and hence often used as an analog to HS.…”

mentioning

confidence: 99%

Highly Sulfated Nonreducing End-derived Heparan Sulfate Domains Bind Fibroblast Growth Factor-2 with High Affinity and Are Enriched in Biologically Active Fractions

Naimy

Buczek‐Thomas

Nugent

et al. 2011

Journal of Biological Chemistry

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Human fibroblast growth factor-2 (FGF2) regulates cellular processes including proliferation, adhesion, motility, and angiogenesis. FGF2 exerts its biological function by binding and dimerizing its receptor (FGFR), which activates signal transduction cascades. Effective binding of FGF2 to its receptor requires the presence of heparan sulfate (HS), a linear polysaccharide with N-sulfated domains (NS) localized at the cell surface and extracellular matrix. HS acts as a platform facilitating the formation of a functional FGF-FGFR-HS ternary complex. Crystal structures of the signaling ternary complex revealed two conflicting architectures. In the asymmetrical model, two FGFs and two FGFRs bind a single HS chain. In contrast, the symmetrical model postulates that one FGF and one FGFR bind to the free end of the HS chain and dimerization require these ends to join, bringing the two half-complexes together. In this study, we screened a hexasaccharide HS library for compositions that are able to bind FGF2. The library was composed primarily of NS domains internal to the HS chain with minor presence of nonreducing end (NRE) NS. The binders were categorized into low versus high affinity binders. The low affinity fraction contained primarily hexasaccharides with low degree of sulfation that were internal to the HS chains. In contrast, the high affinity bound fraction was enriched in NRE oligosaccharides that were considerably more sulfated and had the ability to promote FGFR-mediated cell proliferation. The results suggest a role of the NRE of HS in FGF2 signaling and favor the formation of the symmetrical architecture on short NS domains.

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Controversial glycosaminoglycan conformations

Cited by 85 publications

References 8 publications

Conformational Plasticity in Glycomimetics: Fluorocarbamethyl‐L‐idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings

Conformational Plasticity in Glycomimetics: Fluorocarbamethyl‐L‐idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings

Structural specificity of heparin binding in the fibroblast growth factor family of proteins

Highly Sulfated Nonreducing End-derived Heparan Sulfate Domains Bind Fibroblast Growth Factor-2 with High Affinity and Are Enriched in Biologically Active Fractions

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