Article
- The EMBO Journal (2005) 24, 1655 - 1663
- doi:10.1038/sj.emboj.7600635
Published online: 7 April 2005
Subject Categories:
Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide
Paola Llinas1,a, Marie Hélène Le Du1,a, Henrik Gårdsvoll2, Keld Danø2, Michael Ploug2, Bernard Gilquin1, Enrico A Stura1 and André Ménez1
- CEA, Département d'Ingénierie et d'Etudes des Protéines, CE Saclay, Gif sur Yvette, France
- Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
Correspondence to:
André Ménez, CEA, Département d'Ingénierie et d'Etudes des Protéines, Bât. 152, CE Saclay, 91191 Gif sur Yvette, France. Tel.: +33 1 6908 2603/4263/9052; Fax: +33 1 6908 9071; E-mail: andre.menez@cea.fr
aThese authors contributed equally to this work
Received 17 January 2005; Accepted 3 March 2005
Abstract
We report the crystal structure of a soluble form of human urokinase-type plasminogen activator receptor (uPAR/CD87), which is expressed at the invasive areas of the tumor-stromal microenvironment in many human cancers. The structure was solved at 2.7 Å in association with a competitive peptide inhibitor of the urokinase-type plasminogen activator (uPA)–uPAR interaction. uPAR is composed of three consecutive three-finger domains organized in an almost circular manner, which generates both a deep internal cavity where the peptide binds in a helical conformation, and a large external surface. This knowledge combined with the discovery of a convergent binding motif shared by the antagonist peptide and uPA allowed us to build a model of the human uPA–uPAR complex. This model reveals that the receptor-binding module of uPA engages the uPAR central cavity, thus leaving the external receptor surface accessible for other protein interactions (vitronectin and integrins). By this unique structural assembly, uPAR can orchestrate the fine interplay with the partners that are required to guide uPA-focalized proteolysis on the cell surface and control cell adhesion and migration.
Keywords:
- cancer,
- structure,
- three-finger fold,
- tissue remodelling,
- uPAR
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