Conformational regulation of urokinase receptor function: impact of receptor occupancy and epitope-mapped monoclonal antibodies on lamellipodia induction

TY - JOUR

T1 - Conformational regulation of urokinase receptor function

T2 - impact of receptor occupancy and epitope-mapped monoclonal antibodies on lamellipodia induction

AU - Gårdsvoll, Henrik

AU - Jacobsen, Benedikte

AU - Kriegbaum, Mette C

AU - Behrendt, Niels

AU - Engelholm, Lars

AU - Østergaard, Søren

AU - Ploug, Michael

PY - 2011/9/23

Y1 - 2011/9/23

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Antibodies, Monoclonal

KW - Cell Line

KW - Drosophila melanogaster

KW - Epitope Mapping

KW - Humans

KW - Inhibitory Concentration 50

KW - Kinetics

KW - Ligands

KW - Mice

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Molecular Weight

KW - Peptides

KW - Protein Structure, Secondary

KW - Protein Structure, Tertiary

KW - Pseudopodia

KW - Receptors, Urokinase Plasminogen Activator

KW - Structure-Activity Relationship

KW - Transfection

KW - Urokinase-Type Plasminogen Activator

KW - Vitronectin

U2 - 10.1074/jbc.M111.220087

DO - 10.1074/jbc.M111.220087

M3 - Journal article

C2 - 21799009

SN - 0021-9258

VL - 286

SP - 33544

EP - 33556

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

IS - 38

ER -