Regulation of Extracellular Proteolysis by SERPINS

描述（由申请人提供）：SERPIN生物化学和催化剂具有 最近与基础生物医学研究的其他领域融合，包括 脂代谢和阿尔茨海默病的病理机制，作为一个 由于它们与单一生物实体的共同相互作用， 密度脂蛋白受体相关蛋白（LRP）。低密度脂蛋白 受体相关蛋白是普遍存在的600 kDa细胞表面受体， 作为多种配体的内吞媒介物。LRP及其 家庭成员被认为在疾病的分布中起着关键作用， 细胞表面蛋白，丝氨酸蛋白酶抑制剂， 阿尔茨海默病的病理学、哺乳动物发育和神经细胞 信号在本研究中，我们将利用SERPIN：酶复合物 categories作为一个模型系统，以探讨LRP结构/功能。我们建议 定义LRP及其两种辅助受体肝素的定量作用 硫酸蛋白多糖（HSPG）和尿纤溶酶原激活物受体 （uPAR）在SERPIN的差异催化中，蛋白酶连接蛋白I（PN 1）在 与不同调节蛋白酶的复合物，包括凝血酶、纤溶酶原 激活剂和因子XIa。我们还将研究HSPG的作用， PN 1的内吞后滞留/运输：蛋白酶复合物，一种现象 最近在我们实验室里被描述过。的结构基础 还将研究LRP与PN 1：蛋白酶复合物的相互作用， 制定识别LRP中配体结合位点的策略。 这些信息将用于构建功能丧失的遗传变异体， 将在LRP缺陷型细胞中表达的LRP， 生物功能。最后，我们将扩展我们最近的观察，即PN 1是 凝血蛋白酶FXIa的有效抑制剂。FXIa已经 暗示在淀粉样前体蛋白的代谢中起作用， PN 1：FXIa复合物利用LRP作为清除受体。这就是PN 1， 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学。

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.