Studies on the Effect of Calcium in Interactions Between Heparin and Heparin Cofactor II Using Surface Plasmon Resonance

Zhang, Fuming; Wu, Yi; Ma, Qing; Hoppensteadt, Debra; Fareed, Jawed; Linhardt, Robert J.

doi:10.1177/107602960401000307

Cited by 8 publications

(6 citation statements)

References 21 publications

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“…However, both receptors contain multiple Mg 2ϩ -and Ca 2ϩ -binding sites in their ectodomains, which precludes conclusions on which particular metal ions were required for the binding to heparin. The integrin I domain MIDAS contains one metal ionbinding site (4), which has a 100-fold stronger affinity for Mg 2ϩ than for Ca 2ϩ and thus, at physiological concentrations of these ions, primarily is occupied with Mg 2ϩ (22 -dependent protein binding to heparin has been less frequently observed, one example being heparin cofactor II (24). Thus, it appears that the heparin binding by the ␣X I domain is a rare case of a Mg 2ϩ ion contributing to protein-heparin interaction.…”

Section: Discussionmentioning

confidence: 99%

Binding between the Integrin αXβ2 (CD11c/CD18) and Heparin

Vorup-Jensen

Chi

Gjelstrup

et al. 2007

Journal of Biological Chemistry

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The interactions between cell surface receptors and sulfated glucosamineglycans serve ubiquitous roles in cell adhesion and receptor signaling. Heparin, a highly sulfated polymer of uronic acids and glucosamine, binds strongly to the integrin receptor ␣X␤2 (p150,95, CD11c/CD18). Here, we analyze the structural motifs within heparin that constitute high affinity binding sites for the I domain of integrin ␣X␤2. Heparin oligomers with chain lengths of 10 saccharide residues or higher provide strong inhibition of the binding by the ␣X I domain to the complement fragment iC3b. By contrast, smaller oligomers or the synthetic heparinoid fondaparinux were not able to block the binding. Semipurified heparin oligomers with 12 saccharide residues identified the fully sulfated species as the most potent antagonist of iC3b, with a 1.3 M affinity for the ␣X I domain. In studies of direct binding by the ␣X I domain to immobilized heparin, we found that the interaction is conformationally regulated and requires Mg 2؉ . Furthermore, the fully sulfated heparin fragment induced conformational change in the ectodomain of the ␣X␤2 receptor, also demonstrating allosteric linkage between heparin binding and integrin conformation.Increasing evidence points to an important function of heparin in the immune system. Heparin is exclusively synthesized by connective tissue mast cells and released from storage granula in the inflammatory responses mediated by these leukocytes. Furthermore, several receptors on leukocytes are able to bind with high affinity to heparin. These include the ␤2 integrins ␣M␤2 (Mac-1, CD11b/CD18) and ␣X␤2 (p150,95, CD11c/CD18) (1, 2), which play key roles in the adhesion, migration, and binding of complement fragments by myeloid leukocytes. ␣M␤2 and ␣X␤2 integrins, also referred to as complement receptors 3 and 4, respectively, bind strongly to a protelytic fragment of complement factor 3 designated iC3b, as shown by both cellular and biochemical assays. iC3b plays an important role in phagocytic uptake of microbes by leukocytes of the myeloid lineages. Diamond et al. (2) reported the adhesion of neutrophil granulocytes to heparin-coated surfaces through the ␣M␤2 integrin, which is abundantly expressed on these leukocytes. The ␣X␤2 integrin, primarily expressed on monocytes, macrophages, and dendritic cells, was also demonstrated to support adhesion to heparin by use of cell line transfectants (2).Integrin receptors contain multiple domains in their ectodomain. ␤2 integrins, which in addition to ␣M␤2 and ␣X␤2 include the ␣L␤2 integrin (LFA-1, CD11a/CD18), bind ligands through an inserted (I) domain in the ␣ subunit. Previous studies have indicated a central role for the ␣M and ␣X I domains in binding to heparin (2) and shown that the affinity of the ␣X I domain for heparin is significantly higher than the affinity of the ␣M I domain (3). In the metal ion-dependent adhesion site (MIDAS) 2 of the I domain, a Mg 2ϩ ion forms a crucial bond to an acidic residue in protein ligands. However, the requirement for Mg 2ϩ in...

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Section: Discussionmentioning

confidence: 99%

Binding between the Integrin αXβ2 (CD11c/CD18) and Heparin

Vorup-Jensen

Chi

Gjelstrup

et al. 2007

Journal of Biological Chemistry

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“…Heparan sulfate is distinguished from the closely related heparin mainlyinhaving alower degree of sulfation, alarger proportion of N-acetylated as com- pared to N-sulfatedg lucosamine residues, and in containing mainlyG lcAa si ts uronic acidr ather thant he 70-80% IdoA present in most preparations of heparin (46,47). Due to the presenceofthe carboxylic acid and sulfate functionalgroups,with heparinbeing the most acidicpolysaccharide in the human body (48),t hese compounds areh ighlya nionic polymersand interact with manycationic species,including ions and proteins. It is consideredthat the negative charge thatthese moleculescarry is important in many biologicalprocesses.F or example, the anionic GAGlayer on the luminalendothelial surface helps to restrict plasmap roteinsw ithin the intravascular space.…”

Section: Structureand Anionic Characterofgagsmentioning

confidence: 99%

Glycosaminoglycan: a candidate to stimulate the repair of chronic wounds

Peplow

2005

Thromb Haemost

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A persistent inflammation with large numbers of neutrophils is found in chronic wounds. Secretory products released from the neutrophils, which include proteinases and a heparin-binding protein, are detrimental to wound healing as they cause degradation of the extracellular matrix and growth factors, and promote further recruitment of neutrophils to the wound area. The neutrophil-derived elastase, cathepsin G, proteinase-3 and heparin-binding protein are cationic, and it is hypothesized that their effects can be inhibited by electrostatic binding with certain anionic polymers such as glycosaminoglycans or functionalized dextrans. A sustained delivery of such compounds alone or in combination from a biodegradable carrier may provide a stimulus for these wounds to pass to the next stage of repair.

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“…22,69,70 Because there is a formal charge of +2, it is likely that Mg 2+ and Ca 2+ cations participate in networks with the anionic residues of proteins and/or participate in territorial interactions. 20 It was shown experimentally [71][72][73][74] that heparin -protein interactions are modified through divalent ions such as calcium or magnesium. E.g.…”

Section: Gas Phase Metal Affinitiesmentioning

confidence: 99%

Effect of metal ions (Li+, Na+, K+, Mg2+ and Ca2+) and water on the conformational changes of glycosidic bonds in heparin oligosaccharides

2013

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The effects of complexation by Li + , Na + , K + , Mg 2+ , and Ca 2+ counterions and water on the molecular structure of the Fondaparinux pentameter (D-E-F-G-H) and its dimer units (D-E, E-F, F-G and G-H) are studied using Becke 3LYP hybrid density functional theory and molecular modeling. The ionic charge state, the number of metal ion adducts and the counterion radii are important factors that influence counterioninduced conformational changes in these pentamers and dimers of heparin. The displacement of the Li + , Na + , K + , Mg 2+ and Ca 2+ cations from their binding sites in the salts results in appreciable changes in the anion conformations. The interaction energies are very negative and span a broad range from 21900 to 216 000 kJ mol 21 , which is the result of multiple coordinate bonds between ions and basic centers in glycosaminoglycan units.

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Studies on the Effect of Calcium in Interactions Between Heparin and Heparin Cofactor II Using Surface Plasmon Resonance

Cited by 8 publications

References 21 publications

Binding between the Integrin αXβ2 (CD11c/CD18) and Heparin

Binding between the Integrin αXβ2 (CD11c/CD18) and Heparin

Glycosaminoglycan: a candidate to stimulate the repair of chronic wounds

Effect of metal ions (Li+, Na+, K+, Mg2+ and Ca2+) and water on the conformational changes of glycosidic bonds in heparin oligosaccharides

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