STRUCTURAL STUDY OF HEMATOLOGY-RELATED PROTEINS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们使用X射线结晶学来研究在血液学领域中重要的蛋白质-蛋白质相互作用和蛋白质-膜相互作用。尿激酶型纤溶酶原激活剂(UPA)及其细胞表面受体(UPAR)在细胞表面介导多种生物活性，包括纤溶酶原激活、细胞外基质(ECM)重塑、生长因子激活和启动细胞内信号转导。UPA系统被认为在多种细胞功能中发挥重要作用，包括细胞黏附、迁移、侵袭和趋化，特别是与癌症和炎症相关的疾病过程。UPA系统多效性的分子基础来自两个方面：1)uPAR与多种配体相互作用的能力，包括uPA、Vitronectin、整合素、低密度脂蛋白受体相关蛋白、G蛋白偶联受体等；2)这些蛋白质-蛋白质相互作用引起的动态构象变化。通常不活跃的单链uPA(ScuPA)在与uPAR结合时产生酶活性。此外，与uPAR结合的scuPA和双链uPA(TcuPA)对纤溶酶原激活物抑制剂的敏感性不同，这表明它们在结构和调控方面存在重要差异。我们的目标之一是系统地研究uPAR与其配体之间相互作用的结构基础和动力学性质。

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