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

这一组成部分的广泛和长期目标是使用现代方法 在分子和结构生物学中， 低密度脂蛋白（LDL）受体的结构和功能 （LDLR），并将这种理解与现有的，大的人类- 遗传学数据库（例如，家族性高胆固醇血症的LDLR突变 （FH））。 尽管有大量关于人类遗传学和细胞的信息， LDLR的生物学，我们对这种受体结构的理解 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LDLR，提供 新的突变体和转染的细胞系。 这一部分的具体目标是： (1)了解脂蛋白结合的结构基础， LDLR，并将大量影响结合的突变， 从而导致FH，进入结构和机制的角度。 ] (2)了解配体释放的pH开关的结构基础 酸性内体中的LDLR，以及一些突变 禁用此pH-0开关，导致FH。 (3)为了了解“脂质激活”的结构基础， 载脂蛋白E（apoE），LDLR的高亲和力配体和LDLR- 相关蛋白（LRP，乳糜微粒受体）。

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).