DOMAIN STRUCTURE AND BINDING PROPERTIES OF LDL RECEPTOR AND ITS LIGAND APOE

这一部分的广泛、长期目标是使用现代方法 对分子和结构生物学有一个详细的了解 低密度脂蛋白受体的结构和功能 (LDLR)，并将这种理解与现有的大型人类联系起来- 遗传学数据库(例如，家族性高胆固醇血症的LDLR突变 (FH))。尽管有关于人类遗传学和细胞的丰富信息 低密度脂蛋白受体的生物学，我们对该受体结构的理解 而功能相对原始。我们将广泛地与 第三部分，这将有助于我们分析最不发达国家的情况 新的突变体和转基因细胞系。 这一组成部分的具体目标是： (1)了解脂蛋白结合的结构基础 LDLR，并将影响结合的大量突变，以及 从而导致FH，进入结构和机械的角度。 ] (2)了解pH开关用于配体释放的结构基础 在酸性内体中的LDLR，以及一些突变的机制 禁用此pH-0开关，导致FH。 (3)了解“脂质活化”的结构基础。 载脂蛋白E(ApoE)是低密度脂蛋白受体和低密度脂蛋白受体的高亲和力配体。 相关蛋白(LRP，一种乳胶粒受体)。

The broad, long-term objective of this component is to use modern methods in molecular and structural biology to develop a detailed understanding of the structure and function of the low density lipoprotein (LDL) receptor (LDLR), and to relate this understanding to the existing, large human- genetics database (e.g., LDLR mutations in familial hypercholesterolemia (FH)). Despite the wealth of information about the human genetics and cell biology of LDLR, our understanding of this receptor in terms of structure and function is relatively primitive. We will interact extensively with component III, which will facilitate our analysis of LDLR by providing novel mutants and transfected cell lines. The specific aims of this component are: (1) To understand the structural basis of the binding of lipoproteins by LDLR, and to put the large number of mutations that affect binding, and thereby cause FH, into a structural and mechanistic perspective. ] (2) To understand the structural basis of the pH switch for ligand release by LDLR in acidic endosomes, and the mechanism by which some mutations disable this pH-0switch, resulting in FH. (3) To understand the structural basis for the "lipid activation" of apolipoprotein E (apoE), a high affinity ligand of LDLR and the LDLR- related protein (LRP, a chylomicron receptor).