STRUCTURAL STUDY OF HEMATOLOGY-RELATED PROTEINS

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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. We use X-ray crystallography to study protein-protein interaction and protein-memberane interaction important in hematology field. Urokinase plasminogen activator (uPA) together with its cell surface receptor (uPAR) mediates a variety of biological activities at the cell surface including plasminogen activation, extracellular matrix (ECM) remodeling, growth factor activation and the initiation of intracellular signaling. The uPA system has been recognized as playing an important role in a variety of cellular functions, including cell adhesion, migration, invasion and chemotaxis, especially as they pertain to 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 changes caused by these protein-protein interactions. Single-chain uPA (scuPA) that is usually inactive develops enzymatic activity upon binding with uPAR. Moreover, 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. One of our goals is to systematically study the structural basis and the dynamic nature of the interactions between uPAR and its ligands