Structural Thermodynamics of Human Apolipoprotein C-1

人载脂蛋白 C-1 的结构热力学

• 批准号: 7413796
• 负责人: Olga Gursky
• 金额: $ 9.42万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413796
• 关键词: Accounting; Address; Affect; Amino Acids; Amyloid; Amyloidosis; Antiatherogenic; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein E; Apolipoproteins; Apolipoproteins C; Atherosclerosis; Binding Sites; C-terminal; Cholesterol; Cholesterol Esters; Circular Dichroism; Circular Dichroism Spectroscopy; Complex; Coronary heart disease; Crystallography; Differential Scanning Calorimetry; Disease; Disruption; Electron Microscopy; Fiber; Fluorescence Spectroscopy; Goals; Grant; Height; Helix (Snails); Helix-Turn-Helix Motifs; High Density Lipoproteins; Human; Indium; Individual; Kinetics; Lead; Light-Scattering Spectroscopy; Lipid Binding; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Mediating; Metabolism; Methods; Modeling; Molecular; Molecular Conformation; Mutagenesis; Mutation; Particle Size; Pathogenesis; Pathway interactions; Peptides; Plasma; Play; Point Mutation; Proline; Property; Proteins; Range; Rate; Research; Research Support; Role; Scanning; Series; Shapes; Site; Solutions; Sterol O-Acyltransferase; Stroke; Structure; Structure-Activity Relationship; Testing; Thermodynamics; Time; Triglycerides; Variant; Work; base; ear helix; insight; macromolecule; monomer; mutant; novel; particle; reconstitution; size; uptake

The long-term objective of this project is to determine in molecular detail the energetic-structure-function relationship in exchangeable apolipoproteins and lipoproteins, thereby providing an insight into molecular mechanisms of lipoprotein action in the pathogenesis of atherosclerosis and other Upoprotein-related diseases. Exchangeable apolipoproteins are soluble protein components of lipoproteins that mediate lipid and cholesterol transport and metabolism and play crucial roles in the pathogenesis of atherosclerosis, coronary heart disease, stroke and other major human disorders. Structural stability and compositional variability of lipoproteins are essential for their functions, and have to be understood in detail in order to elucidate molecular mechanisms of lipoprotein action in normal and in diseased states. The proposed work addresses this long-term goal through detailed studies of the energetics, structure and lipid binding function of two small human plasma apolipoproteins, apoC-1 and apoA-2. ApoC-1 delays the clearance of potentially atherogenic triglyceride-rich particles by inhibiting their uptake via the apoE-mediated low-density lipoprotein receptor-related pathway. The ability of apoC-1 to activate lecitin:cholesterol acyltransferase (LCAT) may account for normal plasma levels of cholesterol esters in subjects with deficiency of the major LCAT activator, apoA-1. ApoA-2 ability to displace apoA-1 from high-density lipoproteins (HDL) affects the antiatherogenic functions of HDL. Energetic and structural analyses of lipid-free and lipid-bound human apoA-2, apoC-1 and a series of apoC-1 mutants targeted towards key structural regions will be carried out by using a combination of far- and near-UV circular dichroism and fluorescence spectroscopy, electron microscopy, differential scanning calorimetry, and x-ray diffraction methods. Such analysis will determine, at the level of individual amino acids, the roles of key structural elements in apoC-1 for its folding, stability and lipid binding properties; identify critical determinants for the Lp stability and their relation to the kinetics of apolipoprotein transfer among lipoproteins in the course of lipoprotein metabolism; crystallize apoC-1 and analyze its crystal structure that may provide a model for a functional apolipoprotein conformation. The results will provide the energetic and structural basis for understanding molecular mechanisms of lipoprotein action in normal and diseased states.

该项目的长期目标是在分子细节上确定能量-结构-功能