FIGURE 8.

Conformational switch in uPAR regulating lamellipodia formation. This figure schematically depicts the model we propose for ligand-induced regulation of uPAR-mediated lamellipodia formation on vitronectin-rich matrices. We postulate that there is a considerable inherent conformational flexibility in the multidomain assembly of the three homologous LU domains in uPAR, enabling the receptor to explore different conformational states. The equilibrium between these states is sensitive to mutations as well as engagement of different mAbs and ligands as indicated in the figure. The open conformation is inferred from our functional biochemical data, whereas the intermediate and closed conformations are confirmed by x-ray crystal structures of AE147-uPAR (PDB accession code 1YWH) and ATF-uPAR (PDB accession code 2FD6), respectively. The location of Tyr⁵⁷ at the DI-DII interface is indicated in magenta. Vn, vitronectin.