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

Haydyn D T Mertens, Magnus Kjaergaard, Simon Mysling, Henrik Gårdsvoll, Thomas Jørgensen, Dmitri I Svergun, Michael Ploug

    46 Citationer (Scopus)

    Abstract

    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.
    OriginalsprogEngelsk
    TidsskriftJournal of Biological Chemistry
    Vol/bind287
    Udgave nummer41
    Sider (fra-til)34304-15
    Antal sider12
    ISSN0021-9258
    DOI
    StatusUdgivet - 2012

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