Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide

TY - JOUR

T1 - Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide

AU - Llinas, Paola

AU - Le Du, Marie Hélène

AU - Gårdsvoll, Henrik

AU - Danø, Keld

AU - Ploug, Michael

AU - Gilquin, Bernard

AU - Stura, Enrico A

AU - Ménèz, Andre

PY - 2005/5/4

Y1 - 2005/5/4

N2 - We report the crystal structure of a soluble form of human urokinase-type plasminogen activator receptor (uPAR/CD87), which is expressed at the invasive areas of the tumor-stromal microenvironment in many human cancers. The structure was solved at 2.7 A in association with a competitive peptide inhibitor of the urokinase-type plasminogen activator (uPA)-uPAR interaction. uPAR is composed of three consecutive three-finger domains organized in an almost circular manner, which generates both a deep internal cavity where the peptide binds in a helical conformation, and a large external surface. This knowledge combined with the discovery of a convergent binding motif shared by the antagonist peptide and uPA allowed us to build a model of the human uPA-uPAR complex. This model reveals that the receptor-binding module of uPA engages the uPAR central cavity, thus leaving the external receptor surface accessible for other protein interactions (vitronectin and integrins). By this unique structural assembly, uPAR can orchestrate the fine interplay with the partners that are required to guide uPA-focalized proteolysis on the cell surface and control cell adhesion and migration.

AB - We report the crystal structure of a soluble form of human urokinase-type plasminogen activator receptor (uPAR/CD87), which is expressed at the invasive areas of the tumor-stromal microenvironment in many human cancers. The structure was solved at 2.7 A in association with a competitive peptide inhibitor of the urokinase-type plasminogen activator (uPA)-uPAR interaction. uPAR is composed of three consecutive three-finger domains organized in an almost circular manner, which generates both a deep internal cavity where the peptide binds in a helical conformation, and a large external surface. This knowledge combined with the discovery of a convergent binding motif shared by the antagonist peptide and uPA allowed us to build a model of the human uPA-uPAR complex. This model reveals that the receptor-binding module of uPA engages the uPAR central cavity, thus leaving the external receptor surface accessible for other protein interactions (vitronectin and integrins). By this unique structural assembly, uPAR can orchestrate the fine interplay with the partners that are required to guide uPA-focalized proteolysis on the cell surface and control cell adhesion and migration.

KW - Crystallization

KW - Humans

KW - Molecular Conformation

KW - Peptides

KW - Protein Binding

KW - Receptors, Cell Surface

KW - Receptors, Urokinase Plasminogen Activator

KW - Recombinant Proteins

KW - Urokinase-Type Plasminogen Activator

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/sj.emboj.7600635

DO - 10.1038/sj.emboj.7600635

M3 - Journal article

C2 - 15861141

SN - 0261-4189

VL - 24

SP - 1655

EP - 1663

JO - E M B O Journal

JF - E M B O Journal

IS - 9

ER -