STRUCTURE AND FUNCTION OF HUMAN APOLIPOPROTEIN A-IV

人载脂蛋白A-IV（apo-IV）是一种血浆蛋白， 其独特的性质是它对等离子体表面的不稳定亲和力 脂蛋白 虽然载脂蛋白A-IV在脂质体中的特异性功能 代谢尚未确定，研究，由 主要研究者为越来越多的证据做出了贡献 这表明载脂蛋白A-IV是血管内 高密度脂蛋白（HDL）代谢。 最近的研究表明 载脂蛋白A-IV与脂质表面的不稳定结合可能是 其生理功能。 具体而言，我们建议， 载脂蛋白A-IV与HDL的不稳定结合构成了一种恒压机制 其将HDL的表面压力维持在所需的临界范围内 卵磷脂-胆固醇酰基转移酶（LCAT）的最佳活性， 胆固醇酯转移蛋白（CETP）。 这项提案的目的是调查分子的影响 载脂蛋白A-IV与磷脂相互作用的结构， 特别是CETP反应的分子机理。 我们 因此提出四个具体目标：1）重组apo A-IV缺失 突变体将通过光谱和表面平衡技术进行研究 以检查特定氨基酸结构域对其有序排列的影响， 结构、热力学稳定性和脂质亲和力; 2） 重组载脂蛋白A-IV缺失突变体与磷脂相互作用 将通过物理化学技术进行研究， 蛋白质结构对载脂蛋白A-IV/脂质的性质和LCAT反应性的影响 复合物; 3）CETP和HDL的相互作用将使用 荧光标记的重组和天然HDL，以确定 载脂蛋白A-IV促进CETP催化的脂质交换的机制 和HDL亚种的相互转换; 4）CETP将使用 表面平衡技术来阐明反应机理 载脂蛋白A-IV的作用是促进CETP催化的脂质交换， HDL亚种的相互转换; 4）CETP将使用 表面平衡技术来阐明反应机理 以及载脂蛋白A-IV在脂质交换现象中的作用。 等离子体结构与功能的研究 载脂蛋白已经在诊断，治疗， 和预防动脉粥样硬化性心血管疾病， 美国的死因。 本提案的长期目标是 描述了人载脂蛋白A-IV的生理功能。

Human apolipoprotein A-IV (apo-IV) is a plasma protein whose most distinctive property is its labile affinity for the surface of plasma lipoprotein. Although the specific function of apo A-IV in lipid metabolism has not yet been determined, studies, conducted by the Principal Investigator have contributed to a growing body of evidence which implicates apo A-IV as an important factor in the intravascular metabolism of high density lipoprotein (HDL). Recent studies now suggest that the labile binding of apo A-IV to lipid surfaces may be central to its physiological function. Specifically, we have proposed that the labile binding of apo A-IV to HDL constitutes a barostatic mechanism which maintains the surface pressure of HDL in a critical range required for optimal activity of lecithin-cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP). The purpose of this proposal is to investigate the impact of molecular structure on the interaction of apo A-IV and phospholipid, with particular regard tot he molecular mechanism of the CETP reaction. We therefore propose four specific aims: 1) Recombinant apo A-IV deletion mutants will be studied by spectroscopic and surface balance techniques to examine the effect of specific amino acid domains on its ordered structure, thermodynamic stability, and lipid affinity; 2) The interaction of recombinant apo A-IV deletion mutants and phospholipid will be studied by physico-chemical techniques to examine the impact of protein structure on the properties and LCAT reactivity of apo A-IV/lipid complexes; 3) The interaction of CETP and HDL will be investigated using fluorescent labelled recombinant and native HDL to determine the mechanisms by which apo A-IV facilitates CETP-catalyzed lipid exchanges and the interconversion of HDL subspecies; 4) CETP will be studied using surface balance techniques to elucidate the mechanisms of the reaction and the role of apo A-IV facilitates CETP-catalyzed lipid exchanges and the interconversion of HDL subspecies; 4) CETP will be studied using surface balance techniques to elucidate the mechanisms of the reaction and the role of apo A-IV in lipid exchange phenomena. The investigation of the structure and function of the plasma apolipoproteins has led to major advances in the diagnosis, treatment, and prevention to atherosclerotic cardiovascular disease, the leading cause of death in the USA. The long term goal of this proposal is to delineate the physiological functions of human apo A-IV.