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

LDL受体及其配体APOE的结构域结构和结合特性

• 批准号: 5213715
• 负责人: PETER KIM
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5213715
• 关键词: X ray crystallography; acid base balance; apolipoproteins; gene mutation; hypercholesterolemia; laboratory rabbit; low density lipoprotein receptor; molecular pathology; nuclear magnetic resonance spectroscopy; protein folding; protein structure function; receptor binding; tissue /cell culture

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).

该组件的广泛、长期目标是使用现代方法