Heparan Sulfate:  A Complex Polymer Charged with Biological Activity

Whitelock, John M.; Iozzo, Renato V.

doi:10.1021/cr010213m

Cited by 357 publications

(197 citation statements)

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“…The diffusional anisotropy is the quotient between the parallel and perpendicular correlation times and the most precise method to calculate it is by a complete relaxation analysis using 13 C T 1 , T 2 and heteronuclear NOE, avoiding the influence of the internal correlation times that decrease these ratios. However, this time consuming method could be replaced by the relationship between the correlation times of two orthogonal interprotonic vectors of similar distances aligned with respect to the molecular axis.…”

Section: Paper Organic and Biomolecular Chemistrymentioning

confidence: 99%

“…8 Among them, worth mentioning are the interactions with the fibroblast growth factor (FGF) family, 9 chemokines, 10 antithrombin-III (AT-III), 11 ECM 12 and plasma proteins. 13 In the context of a wider research programme about the factors that regulate the activation of the FGF-FGFR signalling pathway by glycosaminoglycans, some hexa-and octasaccharides related to the structure of heparin and/or heparan sulphate with diverse substitution patterns were prepared, tested, and their structures solved (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study

et al. 2013

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The motional behaviour of heparin oligosaccharides in solution is best described as a top rotor having two perpendicular rotation axes. This prevents an accurate extraction of interprotonic distances by NOESY/ROESY based methods. In this paper, we describe the solution structure of the hexasaccharide 1 calculated from high exactitude distance data obtained from off-resonance ROESY combined with a long MD simulation of 500 ns. In previous studies, we have found that two synthetic hexasaccharides having the sulphate groups directed towards one side of its central plane have an opposite biological activity, while 1 is unable to activate the FGF-1 signalling pathway, the other (2) is even more active than the regular region derived hexasaccharide (3) that mimics the natural active compound, heparin. From the structural analysis it was concluded that 1 has similar three-dimensional characteristics to 2 or 3 and therefore the differences in the activity should be due to the arrangement of the sulphate groups within the hexasaccharidic sequence.

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Section: Paper Organic and Biomolecular Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study

et al. 2013

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“…Accordingly, much attention has been invested in the search for and characterization of anti-angiogenic agents to enable regulated and inhibited tumor angiogenesis as part of cancer therapies (1). The proteoglycan perlecan plays a key role in the angiogenic process, primarily by modulating the availability and activity of growth factors involved in angiogenesis such as fibroblast growth factor 2, VEGF, 3 and platelet-derived growth factor (2)(3)(4)(5)(6). The most C-terminal part of perlecan (domain V), named endorepellin, is a powerful angiogenic inhibitor (7).…”

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confidence: 99%

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

Woodall

Nyström

Iozzo

et al. 2008

Journal of Biological Chemistry

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Endorepellin, the C-terminal module of perlecan, has angiostatic activity. Here we provide definitive genetic and biochemical evidence that the functional endorepellin receptor is the ␣2␤1 integrin. Notably, the specific endorepellin binding to the receptor was cation-independent and was mediated by the ␣2 I domain. We show that the anti-angiogenic effects of endorepellin cannot occur in the absence of ␣2␤1. Microvascular endothelial cells from ␣2␤1 ؊/؊ mice, but not those isolated from either wild-type or ␣1␤1 ؊/؊ mice, did not respond to endorepellin. Moreover, syngeneic Lewis lung carcinoma xenografts in ␣2␤1 ؊/؊ mice failed to respond to systemic delivery of endorepellin. In contrast, endorepellin inhibited tumor growth and angiogenesis in the wild-type mice expressing integrin ␣2␤1. We conclude that the angiostatic effects of endorepellin in vivo are mediated by a specific interaction of endorepellin with the ␣2␤1 integrin receptor.The incorporation of new blood vessels into growing neoplasms is a prerequisite for tumor viability and progression. Accordingly, much attention has been invested in the search for and characterization of anti-angiogenic agents to enable regulated and inhibited tumor angiogenesis as part of cancer therapies (1). The proteoglycan perlecan plays a key role in the angiogenic process, primarily by modulating the availability and activity of growth factors involved in angiogenesis such as fibroblast growth factor 2, VEGF, 3 and platelet-derived growth factor (2-6). The most C-terminal part of perlecan (domain V), named endorepellin, is a powerful angiogenic inhibitor (7). Endorepellin carries three laminin-like globular (LG) domains separated by epidermal growth factor-like repeats (8) and binds to numerous extracellular matrix proteins, growth factors, and receptors including collagen XVIII, fibulin-2, nidogen, fibroblast growth factor 7, fibroblast growth factor-binding protein, ECM1 (7, 9 -12), ␣-dystroglycan, and integrin ␣2␤1 (9, 13-16). The endorepellin anti-angiogenic effect is parallel to several proteolytically released fragments from vascular basement membrane such as endostatin, the NC-1 domain of collagen type XVIII, and tumstatin, the NC-1 domain the of type IV collagen ␣3 chain (8,17,18). These fragments principally act on endothelial cells as "negative" ligands for specific integrin receptors. Endorepellin is a potent inhibitor in several angiogenesis assays such as endothelial cell migration, collagen-induced capillary morphogenesis, blood vessel recruitment into Matrigel plugs, and chicken chorioallontoic membrane (7,19). It also effectively retards in vivo tumor growth by specifically targeting tumor angiogenesis (20). We hypothesize that endorepellin takes effect via the LG3 domain binding to the integrin ␣2␤1 causing actin disassembly and therefore affecting three key steps of angiogenesis: endothelial cell adhesion, migration, and morphogenesis.Here we have further investigated the endorepellin-␣2␤1 integrin interactions by using cell-free experiments with a solub...

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“…They occur covalently bound to core proteins and are ubiquitously expressed at most cell surfaces (9). These molecules are structurally complex, characterized by very large interactive properties, and recognize many unrelated protein via clusters of basic amino acids exposed on the surface of their targets (10). As such, they are exploited as a prevalent source of docking sites by a large array of pathogens (11)(12)(13) that interact with highly sulfated heparin-like regions of these polysaccharides (14).…”

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confidence: 99%

The HIV-1 Envelope Glycoprotein gp120 Features Four Heparan Sulfate Binding Domains, Including the Co-receptor Binding Site

Crublet¹,

Andrieu

Vivès³

et al. 2008

Journal of Biological Chemistry

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It is well established that the human immunodeficiency virus-1 envelope glycoprotein surface unit, gp120, binds to cellassociated heparan sulfate (HS). Virus infectivity is increased by such interaction, and a variety of soluble polyanions efficiently neutralize immunodeficiency virus-1 in vitro. This interaction has been mainly attributed to the gp120 V3 loop. However, although evidence suggested that this particular domain does not fully recapitulate the binding activity of the protein, the ability of HS to bind to other regions of gp120 has not been completely addressed, and the exact localizations of the polysaccharide binding sites are not known. To investigate in more detail the structural basis of the HS-gp120 interaction, we used a mapping strategy and compared the heparin binding activity of wild type and mutant gp120 using surface plasmon resonance-based binding assays. Four heparin binding domains (1-4) were identified in the V2 and V3 loops, in the C-terminal domain, and within the CD4-induced bridging sheet. Interestingly, three of them were found in domains of the protein that undergo structural changes upon binding to CD4 and are involved in co-receptor recognition. In particular, Arg 419 , Lys 421 , and Lys 432 , which directly interact with the co-receptor, are targeted by heparin. This study provides a complete account of the gp120 residues involved in heparin binding and identified several binding surfaces that constitute potential target for viral entry inhibition. Human immunodeficiency virus (HIV)4 gains entry into permissive CD4 ϩ cells by sequentially interacting with CD4, the primary receptor, and a co-receptor, usually either CCR5 or CXCR4 (1). Both receptor and co-receptors are recognized by gp120, the glycoprotein that constitutes the surface unit of HIV envelope spikes. This protein consists of five relatively conserved regions (C1 to C5) that fold into a "core" comprising two distinct domains termed "inner" and "outer" and five variable regions (V1 to V5). This protein is prone to structural changes and is believed to sample a number of different conformations. A wealth of evidence showed that upon binding to CD4, roughly half of the gp120 core structure undergoes structural rearrangements, in particular within the inner domain. In the CD4-bound form, the base of the V1/V2 region of the inner domain (␤2 and ␤3 strands) is brought to close proximity to a ␤-hairpin of the outer domain (␤20 and ␤21 strands) and forms a four-stranded ␤-sheet located within the bridging sheet that connects the inner and the outer domain of the glycoprotein. Importantly, this highly conserved structure forms, in conjunction with the V3 loop, the binding site for CCR5 or CXCR4 (2-7).It has been well known that HIV also binds to CD4 Ϫ cells in a gp120-dependent manner through interactions with cell surface molecules including heparan sulfates (HSs) (8). HSs and the closely related heparin belong to a large family of anionic polysaccharides, collectively known as glycosaminoglycans. They occur covalently bou...

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Heparan Sulfate: A Complex Polymer Charged with Biological Activity

Cited by 357 publications

References 313 publications

3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study

3D structure of a heparin mimetic analogue of a FGF-1 activator. A NMR and molecular modelling study

Integrin α2β1 Is the Required Receptor for Endorepellin Angiostatic Activity

The HIV-1 Envelope Glycoprotein gp120 Features Four Heparan Sulfate Binding Domains, Including the Co-receptor Binding Site

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