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In silico docking of urokinase plasminogen activator and integrins.

ABSTRACT: BACKGROUND: Urokinase, its receptor and the integrins are functionally associated and involved in regulation of cell signaling, migration, adhesion and proliferation. No structural information is available on this potential multimolecular complex. However, the tri-dimensional structure of urokinase, urokinase receptor and integrins is known. RESULTS: We have modeled the interaction of urokinase on two integrins, alphaIIbbeta3 in the open configuration and alphavbeta3 in the closed configuration. We have found that multiple lowest energy solutions point to an interaction of the kringle domain of uPA at the boundary between alpha and beta chains on the surface of the integrins. This region is not far away from peptides that have been previously shown to have a biological role in urokinase receptor/integrins dependent signaling. CONCLUSIONS: We demonstrated that in silico docking experiments can be successfully carried out to identify the binding mode of the kringle domain of urokinase on the scaffold of integrins in the open and closed conformation. Importantly we found that the binding mode was the same on different integrins and in both configurations. To get a molecular view of the system is a prerequisite to unravel the complex protein-protein interactions underlying urokinase/urokinase receptor/integrin mediated cell motility, adhesion and proliferation and to design rational in vitro experiments.

SUBMITTER: Degryse B

PROVIDER: S-EPMC2323671 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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In silico docking of urokinase plasminogen activator and integrins.

Degryse Bernard B Fernandez-Recio Juan J Citro Valentina V Blasi Francescol F Cubellis Maria Vittoria MV

BMC bioinformatics 20080326

<h4>Background</h4>Urokinase, its receptor and the integrins are functionally associated and involved in regulation of cell signaling, migration, adhesion and proliferation. No structural information is available on this potential multimolecular complex. However, the tri-dimensional structure of urokinase, urokinase receptor and integrins is known.<h4>Results</h4>We have modeled the interaction of urokinase on two integrins, alphaIIbbeta3 in the open configuration and alphavbeta3 in the closed c ...[more]

PMID: 18387210

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Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.

Dataset Information

In silico docking of urokinase plasminogen activator and integrins.

Publications

In silico docking of urokinase plasminogen activator and integrins.

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