STRUCTURE AND FUNCTION OF HUMAN APOLIPOPROTEIN A-IV

人载脂蛋白A-IV(apo-IV)是一种血浆蛋白，其最大的 其独特的性质是它对等离子体表面不稳定的亲和力 脂蛋白。尽管载脂蛋白A-IV在脂类中的特殊功能 新陈代谢尚未确定，由 首席调查员为越来越多的证据做出了贡献 这意味着载脂蛋白A-IV是血管内的一个重要因素 高密度脂蛋白的代谢。最近的研究表明 载脂蛋白A-IV与脂类表面的不稳定结合可能是 它的生理功能。具体地说，我们建议 载脂蛋白A-IV与高密度脂蛋白的不稳定结合构成了一种静压机制 它将高密度脂蛋白的表面压力维持在所需的临界范围内 为使卵磷脂-胆固醇酰基转移酶(LCAT)和 胆固醇酯转移蛋白(CETP)。 这项提议的目的是研究分子的影响 载脂蛋白A-IV与磷脂相互作用的结构 特别对CETP反应的分子机理进行了探讨。我们 因此提出四个具体目标：1)重组载脂蛋白A-IV缺失 突变体将通过光谱和表面平衡技术进行研究。 检测特定氨基酸结构域对其有序性的影响 结构、热力学稳定性和脂类亲和力；2) 重组载脂蛋白A-IV缺失突变体与磷脂的相互作用 将通过物理化学技术研究，以检查 蛋白质结构对载脂蛋白A-IV/脂质性质及LCAT活性的影响 3)CETP与高密度脂蛋白的相互作用将用 荧光标记重组人和天然高密度脂蛋白测定 载脂蛋白A-IV促进CETP催化的脂质交换机制 以及高密度脂蛋白亚种间的相互转化；4)CETP将用 表面平衡技术用于阐明反应机理 载脂蛋白A-IV的作用促进CETP催化的脂质交换和 高密度脂蛋白亚种间的相互转化；4)CETP将用 表面平衡技术用于阐明反应机理 以及载脂蛋白A-IV在脂质交换现象中的作用。 血浆的结构和功能的研究 载脂蛋白在诊断、治疗、 和预防动脉粥样硬化性心血管疾病，领先 在美国的死因。这项提议的长期目标是 描述人类载脂蛋白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.