TY - JOUR

T1 - A flexible multidomain structure drives the function of the urokinase-type plasminogen activator receptor (uPAR)

AU - Mertens, Haydyn D.T.

AU - Kjærgaard, Magnus

AU - Mysling, Simon

AU - Gårdsvoll, Henrik

AU - Jørgensen, Thomas J. D.

AU - Svergun, Dimitri I.

AU - Ploug, Michael

PY - 2012

Y1 - 2012

N2 - 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 as 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 for 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.

AB - 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 as 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 for 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.

U2 - 10.1074/jbc.M112.398404

DO - 10.1074/jbc.M112.398404

M3 - Journal article

C2 - 22896701

VL - 287

SP - 34304

EP - 34315

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 41

ER -