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 - 2012/10/5
Y1 - 2012/10/5
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 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.
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 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.
U2 - 10.1074/jbc.M112.398404
DO - 10.1074/jbc.M112.398404
M3 - Journal article
C2 - 22896701
SN - 0021-9258
VL - 287
SP - 34304
EP - 34315
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 41
ER -