Abstract
The urokinase-type plasminogen activator receptor (uPAR) is a glycolipid-anchored membrane protein with an established role in focalizing uPA-mediated plasminogen activation on cell surfaces. Distinct from this function, uPAR also modulates cell adhesion and migration on vitronectin-rich matrices. Although uPA and vitronectin engage structurally distinct binding sites on uPAR, they nonetheless cooperate functionally, as uPA binding potentiates uPAR-dependent induction of lamellipodia on vitronectin matrices. We now present data advancing the possibility that it is the burial of the β-hairpin in uPA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized by engagement of the β-hairpin in uPA, favors the proper assembly of an active, compact receptor structure that stimulates lamellipodia induction on vitronectin. This molecular model has wide implications for drug development targeting uPAR function.
Highlights
Controlled cell migration is a decisive factor for a plethora of important biological processes that occur during development and adulthood
In accordance with previous studies [9, 11, 21], we found that stably transfected HEK293 cells expressing uPARwt exhibited a pronounced interaction with vitronectin-coated coverslips, causing flattening of the cell body and extensive formation of lamellipodia (Fig. 1)
In the crystal structure solved for the somatomedin B domain (SMB)-urokinase-type plasminogen activator receptor (uPAR)-ATF complex [17], Trp32 is buried in the vitronectin binding interface, and its mutation to alanine obviously impairs this interaction significantly, whereas the affinity for urokinase-type plasminogen activator (uPA) is unaffected [18]
Summary
Controlled cell migration is a decisive factor for a plethora of important biological processes that occur during development and adulthood. Controlled cell migration is intimately involved in both maintenance and dynamic remodeling of tissue architectures during, e.g. wound healing and mammary gland development [1] These processes are executed and tightly regulated via a complicated cross-talk between specific cell surface receptors (e.g. integrins) and insoluble protein components deposited in the extracellular matrix. Five genes are recognized so far to encode proteins with multiple LU domains, and these are all confined to a small gene cluster located on chromosome 19q13 [14] Among these modular proteins, the structure of only uPAR has presently been solved [7, 15,16,17], and it reveals that all three LU domains in this receptor adopt the archetypical three-finger fold that is found in the snake venom ␣-neurotoxins. We have revisited this molecular interplay guided by the structural data obtained recently on this ternary complex [17, 18], and we present independent functional data pointing to a crucial role of the molecular flexibility in uPAR
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