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Optimizing the Genetic Incorporation of Chemical Probes into GPCRs for Photo-crosslinking Mapping and Bioorthogonal Chemistry in Live Mammalian Cells
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Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide

Paola Llinas1, Marie Hélène Le Du, Henrik Gårdsvoll

  • 1CEA, Département d'Ingénierie et d'Etudes des Protéines, CE Saclay, Gif sur Yvette, France.

The EMBO Journal
|April 30, 2005
PubMed

Insights

We determined the crystal structure of human urokinase-type plasminogen activator receptor (uPAR/CD87), revealing its role in cancer invasion. The structure elucidates how uPAR interacts with urokinase-type plasminogen activator (uPA) and other proteins.

Area of Science:

  • Structural Biology
  • Cancer Biology
  • Molecular Medicine

Background:

  • The urokinase-type plasminogen activator receptor (uPAR/CD87) is upregulated in the tumor microenvironment of many cancers.
  • uPAR plays a critical role in cancer cell invasion, adhesion, and migration by interacting with urokinase-type plasminogen activator (uPA).

Purpose of the Study:

  • To elucidate the structural basis of uPA-uPAR interactions.
  • To understand how uPAR mediates cell surface proteolysis and influences cancer progression.

Main Methods:

  • X-ray crystallography was used to determine the structure of soluble human uPAR/CD87.
  • A competitive peptide inhibitor was used to co-crystallize with uPAR.
  • Computational modeling was employed to build a model of the human uPA-uPAR complex.

Main Results:

  • The crystal structure of uPAR was solved at 2.7 Å resolution, revealing a unique three-finger domain organization forming an internal cavity and an external surface.
  • A convergent binding motif was identified, shared by the peptide inhibitor and uPA, which binds within the uPAR internal cavity.
  • The uPA-uPAR complex model shows uPA's receptor-binding module engaging the uPAR cavity, leaving the external surface available for interactions with vitronectin and integrins.

Conclusions:

  • uPAR's structure facilitates a unique assembly that orchestrates interactions with multiple partners.
  • This structural understanding provides insights into uPAR's role in guiding uPA-mediated proteolysis and regulating cell behavior in cancer.

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