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, alpha IIb beta 3 in the open configuration and alpha v beta 3 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.

In silico docking of urokinase plasminogen activator and integrins / B. Degryse, J. Fernandez-Recio, V. Citro, F. Blasi, M.V. Cubellis. - In: BMC BIOINFORMATICS. - ISSN 1471-2105. - 9:Suppl. 2(2008), pp. S8.1-S8.9.

In silico docking of urokinase plasminogen activator and integrins

V. Citro;
2008

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, alpha IIb beta 3 in the open configuration and alpha v beta 3 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.
crystal-structure; cell-adhesion; extracellular segment; receptor-binding; structural basis; migration; complex; upar; alpha-V-beta-3; peptide
Settore BIO/10 - Biochimica
Settore MED/04 - Patologia Generale
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/724727
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