Heparan sulphate with no affinity for antithrombin III and the control of haemostasis

Scully, Michael; Ellis, Vincent; Kakkar, Vijay V.

doi:10.1016/0014-5793(88)81020-2

Cited by 10 publications

(10 citation statements)

References 21 publications

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“…The existence of discrete subspecies of heparin with high affinity for a particular protein have been documented by several groups. AT 111-specific heparin has been isolated by affinity chromatography (Andrade- Gordon and Strickland, 1986;Scully et al, 1988;Kim and Linhardt, 1989;Sudhalter et al, 1989), and results in highly anticoagulant heparin, but does not modulate heparin's effect on cell proliferation (Murrell et al, 1989;Sudhalter et al, 1989) or fibrinolysis (Andrade-Gordon and Strickland, 1986). Other investigators have isolated heparin fractions expressing high affinity to fibronectin (Falcone and Salisbury, 1988), heparin-cofactor I1 (Kim and Linhardt, 1989), tissue plasminogen activator (tPA)(Andrade-Gordon and Strickland, 1990), and acidic FGF (Barzu et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor‐β1 is a heparin‐binding protein: Identification of putative heparin‐binding regions and isolation of heparins with varying affinity for TGF‐β1

McCaffrey

Falcone

1992

Journal Cellular Physiology

175

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Previous studies indicated that a major factor in heparin's ability to suppress the proliferation of vascular smooth muscle cells is an interaction with transforming growth factor-beta 1 (TGF-beta 1). Heparin appeared to bind directly to TGF-beta 1 and to prevent the association of TGF-beta 1 with alpha 2-macroglobulin (alpha 2-M). The present studies indicate that 20-70% of iodinated TGF-beta 1 binds to heparin-Sepharose and the retained fraction is eluted with approximately 0.37 M NaCl. Native, unlabelled platelet TGF-beta 1, however, is completely retained by heparin-Sepharose and eluted with 0.9-1.2 M NaCl. Using synthetic peptides, the regions of TGF-beta 1 that might be involved in the binding of heparin and other polyanions were examined. Sequence analysis of TGF-beta 1 indicated three regions with a high concentration of basic residues. Two of these regions had the basic residues arranged in a pattern homologous to reported consensus heparin-binding regions of other proteins. The third constituted a structurally novel pattern of basic residues. Synthetic peptides homologous to these three regions, but not to other regions of TGF-beta 1, were found to bind to heparin-Sepharose and were eluted with 0.15 M-0.30 M NaCl. Only two of these regions were capable of blocking the binding of heparin to 125I-TGF-beta. Immobilization of these peptides, followed by affinity purification of heparin, indicated that one peptide was capable of isolating subspecies of heparin with high and low affinity for authentic TGF-beta 1. The ability of TGF-beta 1 to bind to heparin or related proteoglycans under physiological conditions may be useful in understanding the biology of this pluripotent growth and metabolic signal. Conversely, a subspecies of heparin molecules with high affinity for TGF-beta 1 may be a factor in some of the diverse biological actions of heparin.

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Section: Discussionmentioning

confidence: 99%

Transforming growth factor‐β1 is a heparin‐binding protein: Identification of putative heparin‐binding regions and isolation of heparins with varying affinity for TGF‐β1

McCaffrey

Falcone

1992

Journal Cellular Physiology

175

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“…tor Xa activity at an injury site and thereby reinforce the role of these glycosaminoglycans as cofactors in antithrombin regulation of factor Xa (30). It should be noted in this regard that heparan sulfate glycosaminoglycans containing specific pentasaccharide binding sequences for antithrombin are limiting in vivo and that chains lacking these sequences may be the major physiologic activators of antithrombin (31)(32)(33). It is therefore of potential physiologic relevance that heparin glycosaminoglycans lacking antithrombin binding sequences accelerate ZPI and antithrombin reactions with factor Xa to comparable extents even at the 30-fold higher plasma concentrations of antithrombin over ZPI.…”

Section: Discussionmentioning

confidence: 99%

Heparin Is a Major Activator of the Anticoagulant Serpin, Protein Z-dependent Protease Inhibitor

Huang

Rezaie

Broze

et al. 2011

Journal of Biological Chemistry

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Protein Z-dependent protease inhibitor (ZPI) is a recently identified member of the serpin superfamily that functions as a cofactor-dependent regulator of blood coagulation factors Xa and XIa. Here we provide evidence that, in addition to the established cofactors, protein Z, lipid, and calcium, heparin is an important cofactor of ZPI anticoagulant function. Heparin produced 20 -100-fold accelerations of ZPI reactions with factor Xa and factor XIa to yield second order rate constants approaching the physiologically significant diffusion limit (k a ‫؍‬ 10 6 to 10The dependence of heparin accelerating effects on heparin concentration was bell-shaped for ZPI reactions with both factors Xa and XIa, consistent with a template-bridging mechanism of heparin rate enhancement. Maximal accelerations of ZPI-factor Xa reactions required calcium, which augmented the heparin acceleration by relieving Gla domain inhibition as previously shown for heparin bridging of the antithrombin-factor Xa reaction. Heparin acceleration of both ZPIprotease reactions was optimal at heparin concentrations and heparin chain lengths comparable with those that produce physiologically significant rate enhancements of other serpin-protease reactions. Protein Z binding to ZPI minimally affected heparin rate enhancements, indicating that heparin binds to a distinct site on ZPI and activates ZPI in its physiologically relevant complex with protein Z. Taken together, these results suggest that whereas protein Z, lipid, and calcium cofactors promote ZPI inhibition of membrane-associated factor Xa, heparin activates ZPI to inhibit free factor Xa as well as factor XIa and therefore may play a physiologically and pharmacologically important role in ZPI anticoagulant function.

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“…Other gD-type 3- O -sulfotransferases can create AT-type heparan sulfate as well, albeit much less efficiently than Hs3st-1 (Girardin et al, 2005; HajMohammadi et al, 2003). Second, studies have shown that suboptimal heparan sulfate structures, including those without 3- O -sulfation, may activate antithrombin sufficiently to maintain hemostasis (Nordenman et al, 1978; Richard et al, 2009; Scully et al, 1988; Streusand et al, 1995). …”

Section: Biochemical and Physiological Implications Of 3-o-sulfationmentioning

confidence: 99%

Heparan sulfate 3-O-sulfation: A rare modification in search of a function

Thacker¹,

Xu²,

Lawrence³

et al. 2014

Matrix Biology

196

244

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Many protein ligands bind to heparan sulfate, which results in their presentation, protection, oligomerization or conformational activation. Binding depends on the pattern of sulfation and arrangement of uronic acid epimers along the chains. Sulfation at the C3 position of glucosamine is a relatively rare, yet biologically significant modification, initially described as a key determinant for binding and activation of antithrombin and later for infection by Type I Herpes Simplex virus. In mammals, a family of seven heparan sulfate 3-O-sulfotransferases installs sulfate groups at this position and constitutes the largest group of sulfotransferases involved in heparan sulfate formation. However, to date very few proteins or biological systems have been described that are influenced by 3-O-sulfation. This review describes our current understanding of the prevalence and structure of 3-O-sulfation sites, expression and substrate specificity of the 3-O-sulfotransferase family and the emerging roles of 3-O-sulfation in biology.

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Heparan sulphate with no affinity for antithrombin III and the control of haemostasis

Cited by 10 publications

References 21 publications

Transforming growth factor‐β1 is a heparin‐binding protein: Identification of putative heparin‐binding regions and isolation of heparins with varying affinity for TGF‐β1

Transforming growth factor‐β1 is a heparin‐binding protein: Identification of putative heparin‐binding regions and isolation of heparins with varying affinity for TGF‐β1

Heparin Is a Major Activator of the Anticoagulant Serpin, Protein Z-dependent Protease Inhibitor

Heparan sulfate 3-O-sulfation: A rare modification in search of a function

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