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A flexible multidomain structure drives the function of the urokinase-type plasminogen activator receptor (uPAR)

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  • Haydyn D T Mertens, Finsen Laboratory, Rigshospitalet and Biotech Research and Innovation Centre (BRIC), Copenhagen Biocenter, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
  • ,
  • Magnus Kjærgaard
  • Simon Mysling, Institut for Biokemi og Molekylær Biologi, Denmark
  • Henrik Gårdsvoll, Institut for Klinisk Medicin, Denmark
  • Thomas J D Jørgensen
  • ,
  • Dmitri I Svergun
  • ,
  • Michael Ploug
The urokinase-type plasminogen activator receptor (uPAR) provides a rendezvous between proteolytic degradation of the extracellular matrix and integrin-mediated adhesion to vitronectin. These processes are, however, tightly linked because the high affinity binding of urokinase regulates the binding of uPAR to matrix-embedded vitronectin. Although crystal structures exist to define the corresponding static bi- and trimolecular receptor complexes, it is evident that the dynamic property of uPAR plays a decisive role in its function. In the present study, we combine small angle x-ray scattering, hydrogen-deuterium exchange, and surface plasmon resonance to develop a structural model describing the allosteric regulation of uPAR. We show that the flexibility of its N-terminal domain provides the key for understanding this allosteric mechanism. Importantly, our model has direct implications for understanding uPAR-assisted cell adhesion and migration as well as for translational research, including targeted intervention therapy and non-invasive tumor imaging in vivo.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume287
Issue41
Pages (from-to)34304-15
Number of pages12
ISSN0021-9258
DOIs
Publication statusPublished - 5 Oct 2012
Externally publishedYes

    Research areas

  • Allosteric Regulation, Animals, Cell Adhesion, Cell Line, Cell Movement, Deuterium Exchange Measurement, Drosophila melanogaster, Extracellular Matrix, Humans, Neoplasm Invasiveness, Neoplasms, Protein Binding, Protein Structure, Tertiary, Proteolysis, Receptors, Urokinase Plasminogen Activator, Scattering, Radiation, Structure-Activity Relationship, Vitronectin, X-Rays

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