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Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site
Heparanase is an endoglycosidase that participates in morphogenesis, tissue repair, heparan sulphates turnover and immune response processes. It is over-expressed in tumor cells favoring the metastasis as it penetrates the endothelial layer that lines blood vessels and facilitates the metastasis by...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913942/ https://www.ncbi.nlm.nih.gov/pubmed/27322195 http://dx.doi.org/10.1371/journal.pone.0157834 |
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author | Bohdan, Nataliya Espín, Salvador Águila, Sonia Teruel-Montoya, Raúl Vicente, Vicente Corral, Javier Martínez-Martínez, Irene |
author_facet | Bohdan, Nataliya Espín, Salvador Águila, Sonia Teruel-Montoya, Raúl Vicente, Vicente Corral, Javier Martínez-Martínez, Irene |
author_sort | Bohdan, Nataliya |
collection | PubMed |
description | Heparanase is an endoglycosidase that participates in morphogenesis, tissue repair, heparan sulphates turnover and immune response processes. It is over-expressed in tumor cells favoring the metastasis as it penetrates the endothelial layer that lines blood vessels and facilitates the metastasis by degradation of heparan sulphate proteoglycans of the extracellular matrix. Heparanase may also affect the hemostatic system in a non-enzymatic manner, up-regulating the expression of tissue factor, which is the initiator of blood coagulation, and dissociating tissue factor pathway inhibitor on the cell surface membrane of endothelial and tumor cells, thus resulting in a procoagulant state. Trying to check the effect of heparanase on heparin, a highly sulphated glycosaminoglycan, when it activates antithrombin, our results demonstrated that heparanase, but not proheparanase, interacted directly with antithrombin in a non-covalent manner. This interaction resulted in the activation of antithrombin, which is the most important endogenous anticoagulant. This activation mainly accelerated FXa inhibition, supporting an allosteric activation effect. Heparanase bound to the heparin binding site of antithrombin as the activation of Pro41Leu, Arg47Cys, Lys114Ala and Lys125Alaantithrombin mutants was impaired when it was compared to wild type antithrombin. Intrinsic fluorescence analysis showed that heparanase induced an activating conformational change in antithrombin similar to that induced by heparin and with a K(D) of 18.81 pM. In conclusion, under physiological pH and low levels of tissue factor, heparanase may exert a non-enzymatic function interacting and activating the inhibitory function of antithrombin. |
format | Online Article Text |
id | pubmed-4913942 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49139422016-07-06 Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site Bohdan, Nataliya Espín, Salvador Águila, Sonia Teruel-Montoya, Raúl Vicente, Vicente Corral, Javier Martínez-Martínez, Irene PLoS One Research Article Heparanase is an endoglycosidase that participates in morphogenesis, tissue repair, heparan sulphates turnover and immune response processes. It is over-expressed in tumor cells favoring the metastasis as it penetrates the endothelial layer that lines blood vessels and facilitates the metastasis by degradation of heparan sulphate proteoglycans of the extracellular matrix. Heparanase may also affect the hemostatic system in a non-enzymatic manner, up-regulating the expression of tissue factor, which is the initiator of blood coagulation, and dissociating tissue factor pathway inhibitor on the cell surface membrane of endothelial and tumor cells, thus resulting in a procoagulant state. Trying to check the effect of heparanase on heparin, a highly sulphated glycosaminoglycan, when it activates antithrombin, our results demonstrated that heparanase, but not proheparanase, interacted directly with antithrombin in a non-covalent manner. This interaction resulted in the activation of antithrombin, which is the most important endogenous anticoagulant. This activation mainly accelerated FXa inhibition, supporting an allosteric activation effect. Heparanase bound to the heparin binding site of antithrombin as the activation of Pro41Leu, Arg47Cys, Lys114Ala and Lys125Alaantithrombin mutants was impaired when it was compared to wild type antithrombin. Intrinsic fluorescence analysis showed that heparanase induced an activating conformational change in antithrombin similar to that induced by heparin and with a K(D) of 18.81 pM. In conclusion, under physiological pH and low levels of tissue factor, heparanase may exert a non-enzymatic function interacting and activating the inhibitory function of antithrombin. Public Library of Science 2016-06-20 /pmc/articles/PMC4913942/ /pubmed/27322195 http://dx.doi.org/10.1371/journal.pone.0157834 Text en © 2016 Bohdan et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Bohdan, Nataliya Espín, Salvador Águila, Sonia Teruel-Montoya, Raúl Vicente, Vicente Corral, Javier Martínez-Martínez, Irene Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site |
title | Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site |
title_full | Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site |
title_fullStr | Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site |
title_full_unstemmed | Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site |
title_short | Heparanase Activates Antithrombin through the Binding to Its Heparin Binding Site |
title_sort | heparanase activates antithrombin through the binding to its heparin binding site |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913942/ https://www.ncbi.nlm.nih.gov/pubmed/27322195 http://dx.doi.org/10.1371/journal.pone.0157834 |
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