THE STRUCTURE OF MODEL LIPOPROTEINS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。脂蛋白将胆固醇和甘油三酯运输到全身的细胞外空间。含有载脂蛋白a - i和载脂蛋白（apo） E的小圆盘状脂蛋白在逆向胆固醇运输中起主要作用，这是一种将胆固醇从动脉粥样硬化病变中去除的机制。在神经元发育和修复过程中，含apoe的脂蛋白在脂质运输中也起着关键作用。虽然apoA-I和apoE的无脂结构已经通过x射线晶体学确定，但在其生理相关状态下，缺乏与脂质相关的载脂蛋白的详细结构信息。为了填补这一空白，我们已经结晶了模型apoa - 1脂蛋白，它在逆向胆固醇运输中具有活性，衍射到20°c和生理活性apoE脂蛋白衍射到8°c。我们也在继续我们的无脂apoE的研究。最近有研究表明，无脂apoE的cooh末端结构域的细胞内切割与细胞骨架破坏和阿尔茨海默病特征的神经元细胞死亡类型相关。由于cooh末端结构域的结构是未知的，我们正在确定有毒片段（残基223-272）的结构和完整的cooh末端结构域，以了解片段细胞毒性的结构基础。作为我们对apoE的兴趣的结果，我们也在研究受体相关蛋白（RAP）的结构。RAP是低密度脂蛋白（LDL）受体家族某些成员表达所必需的伴侣蛋白，也是LDL受体家族成员的通用配体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lipoproteins transport cholesterol and triglycerides throughout the extracellular spaces of the body. Small disc-shaped lipoproteins containing apolipoprotein A-I and apolipoprotein (apo) E play in a major role in reverse cholesterol transport, a mechanism by which cholesterol is removed from atherosclerotic lesions. ApoE-containing lipoproteins also play a key role in transporting lipid during neuronal development and repair. Although lipid-free structures of both apoA-I and apoE have been determined by x-ray crystallography, there is a lack of detailed structural information of either apolipoprotein associated with lipid in their physiologically relevant states. To fill this void, we have crystallized model apoA-I lipoproteins that are active in reverse cholesterol transport that diffract to 20 ¿¿and physiologically active apoE lipoproteins that diffract to 8 ¿¿ We are also continuing our studies of lipid-free apoE. It has been recently shown that intracellular cleavage of the COOH-terminal domain of lipid-free apoE is associated cytoskeletal disruption and the type of neuronal cell death characteristic of Alzheimer's disease. Since the structure of the COOH-terminal domain is unknown, we are determining the structure of the toxic fragment (residues 223-272) and the intact COOH-terminal domain in order to understand the structural basis of the fragment's cellular toxicity. As an outgrowth of our interest in apoE, we also working on the structure of receptor associated protein (RAP). RAP is a chaperone that is required for expression of some members of the low-density lipoprotein (LDL) receptor family and is a universal ligand for member of the LDL-receptor family.