Title : Crystal structure of the urokinase
receptor in a ligand-free form
Abstract :
- The urokinase receptor urokinase-type plasminogen activator receptor ( uPAR ) is a surface receptor capable of not only focalizing urokinase-type plasminogen activator ( uPA )-mediated fibrinolysis to the pericellular micro-environment but also promoting cell migration and chemotaxis
- Consistent with this multifunctional role, uPAR binds several extracellular ligands, including uPA and vitronectin
- Structural studies suggest that uPAR possesses structural flexibility
- It is, however, not clear whether this flexibility is an inherent property of the uPAR structure per se or whether it is induced upon ligand binding
- The crystal structure of human uPAR in its ligand-free state would clarify this issue, but such information remains unfortunately elusive
- We now report the crystal structures of a stabilized, human uPAR (H47C/N259C) in its ligand-free form to 2.4 Å and in complex with amino-terminal fragment ( ATF ) to 3.2 Å
- The structure of uPAR (H47C/N259C) in complex with ATF resembles the wild-type uPAR · ATF complex, demonstrating that these mutations do not perturb the uPA binding properties of uPAR
- The present structure of uPAR (H47C/N259C) provides the first structural definition of uPAR in its ligand-free form, which represents one of the biologically active conformations of uPAR as defined by extensive biochemical studies
- The domain boundary between uPAR DI-DII domains is more flexible than the DII-DIII domain boundary
- Two important structural features are highlighted by the present uPAR structure
- First, the DI-DIII domain boundary may face the cell membrane
- Second, loop 130-140 of uPAR plays a dynamic role during ligand loading/unloading
- Together, these studies provide new insights into uPAR structure-function relationships, emphasizing the importance of the inter-domain dynamics of this modular receptor