UROKINASE-VITRONECTIN COMPLEX

Brookhaven Science Assoc-Brookhaven Lab, Upton NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Urokinase plasminogen activator (uPA) together with its cell surface receptor (uPAR) mediates a variety of biological activities on cell surface including plasminogen activation, extracellular matrix (ECM) remodeling, growth factor activation and the initiation of intracellular signaling. The uPA system plays important roles in a variety of cellular functions, including cell adhesion, migration, invasion and chemotaxis. Moreover, it is implicated in several disease processes involved in cancer and inflammation. The molecular basis that underlies the pleiotropic activities of the uPA system stems from two aspects: 1) the ability of uPAR to interact with many ligands including uPA, vitronectin, integrins, low-density lipoprotein receptor-related protein, G-protein coupled receptor and others;2) the dynamic conformational flexibility caused by these protein-protein interactions. Single-chain uPA (scuPA) that is usually inactive develops enzymatic activity upon binding with uPAR. In addition, scuPA and two-chain uPA (tcuPA) bound to uPAR differ in their susceptibility to plasminogen activator inhibitors, suggesting important differences in their structure and regulation. Several uPAR-ligand complexes have now been crystallized. One of them was published recently (Huai, et al., [unreadable][unreadable][unreadable][unreadable][unreadable]SStructure of Human Urokinase Plasminogen Activator in Complex with its Receptor[unreadable][unreadable][unreadable][unreadable][unreadable]?, Science, 2006, 311:656-9). Our goal is to systematically study the structural basis and the dynamic nature of the interactions between uPAR and its ligands. The complex of uPAR and urokinase (uPA) has been suggested as a potential target for the anti-invasive and anti-metastatic therapy. The structural studies of these uPAR-ligand complexes will reveal the molecular structure of uPAR and the structural basis of interactions between uPAR and its ligands, which will provide a platform for the rational design of uPAR-uPA inhibitors to interrupt the pathophysiological consequences mediated by this interaction.