Regulation of Extracellular Proteolysis by SERPINS

描述(申请人提供)：SERPIN生化和分解代谢 最近与基础生物医学研究的其他领域融合在一起，包括 脂代谢与阿尔茨海默病的发病机制 它们与单一生物实体共同作用的结果；低 密度脂蛋白受体相关蛋白(LRP)。低密度脂蛋白 受体相关蛋白是一种普遍存在的600 kDa细胞表面受体， 作为不同数量的配体的内吞载体。LRP及其智能交通系统 家庭成员被认为在疾病的传播中发挥了关键作用 细胞表面蛋白，丝氨酸蛋白酶抑制物(SERPIN)分解代谢， 阿尔茨海默病的病理学、哺乳动物发育和神经细胞 发信号。在目前的研究中，我们将使用SERPIN：酶复合体 分解代谢作为研究LRP结构/功能的模型系统。我们建议 确定LRP及其两个辅助受体--肝素的定量作用 硫酸蛋白多糖与尿纤溶酶原激活物受体 (UPAR)在SERPIN的差异分解代谢中，蛋白酶Nexin I(PN 1)在 具有不同调节酶的复合体，包括凝血酶、纤溶酶原 激活剂和夏因子。我们还将调查HSPG在 PN1的内吞后滞留/运输：蛋白酶复合体，一种现象 这是我们实验室最近描述的。的结构基础 LRP与PN1：蛋白酶复合体的相互作用也将被研究 制定在LRP中识别配体结合位点的策略。 这些信息将被用来构建功能丧失的遗传变异 将在LRP缺陷细胞中表达的LRP并检测 生物功能。最后，我们将扩大我们最近的观察结果，即PN1是 一种有效的凝血蛋白水解酶抑制剂FXIa。Fxia一直是 与淀粉样前体蛋白的新陈代谢有关， PN1：FXIa复合体利用LRP作为清除受体。这就是PN1， Fxia、APP和LRP在一个共同的生化途径中可能直接 参与阿尔茨海默病的病理研究。

DESCRIPTION(provided by applicant): SERPIN biochemistry and catabolism has recently converged with other areas of basic biomedical research, including lipid metabolism and the mechanism of Alzheimer's Disease pathology, as a result of their common interaction with a single biological entity; the low density lipoprotein receptor-related protein (LRP). The low density lipoprotein receptor-related protein is a ubiquitous, 600 kDa cell surface receptor that acts an endocytosis vehicle for a diverse number of ligands. The LRP and its family members have been implicated as playing key roles in the distribution of cell surface proteins, serine protease inhibitor (SERPIN) catabolism, the pathology of Alzheimer's disease, mammalian development, and neuronal cell signaling. In the present studies we will utilize SERPIN:Enzyme complex catabolism as a model system to probe LRP structure/function. We propose to define the quantitative role of the LRP and two of its co-receptors, heparin sulfate proteoglycans (HSPG's) and the urinary plasminogen activator receptor (uPAR) in the differential catabolism of the SERPIN, protease nexin I (PN 1) in complex with different regulatory proteases including thrombin, plasminogen activator and factor XIa. We will also investigate the role of HSPG's in the post-endocytic retention/trafficking of PN1 :Protease complexes, a phenomenon that was recently described in our laboratory. The structural basis for the interaction of the LRP with PN1:Protease complexes will also be investigated to develop strategies for the identification for ligand binding sites in the LRP. This information will be used to construct loss of function genetic variants of the LRP that will be expressed in LRP deficient cells and assayed for biological function. Finally, we will extend our recent observation that PN1 is a potent inhibitor of the blood coagulation protease, FXIa. FXIa has been implicated to play a role in the metabolism of the amyloid precursor protein, and PN1 :FXIa complexes utilize the LRP as clearance receptor. This places PN1, FXIa, APP and the LRP in a common biochemical pathway that may be directly involved in Alzheimer's disease pathology.