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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, Danmark
  • Henrik Gårdsvoll, Institut for Klinisk Medicin, Danmark
  • 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.
TidsskriftJournal of Biological Chemistry
Sider (fra-til)34304-15
Antal sider12
StatusUdgivet - 5 okt. 2012
Eksternt udgivetJa

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