A flexible multidomain structure drives the function of the urokinase-type plasminogen activator receptor (uPAR).
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.
Finsen Laboratory, Rigshospitalet and Biotech Research and Innovation Centre (BRIC), Copenhagen Biocenter, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
Haydyn D T
HD
Mertens
Magnus
M
Kjaergaard
Simon
S
Mysling
Henrik
H
Gårdsvoll
Thomas J D
TJ
Jørgensen
Dmitri I
DI
Svergun
Michael
M
Ploug
D000494:Allosteric Regulation; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D041961:Deuterium Exchange Measurement; D004331:Drosophila melanogaster; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D055293:Receptors, Urokinase Plasminogen Activator / Q000737:chemistry / Q000378:metabolism; D012542:Scattering, Radiation; D013329:Structure-Activity Relationship; D019096:Vitronectin / Q000737:chemistry / Q000378:metabolism; D014965:X-Rays
D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin