THE STRUCTURE OF MODEL LIPOPROTEINS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。脂蛋白将胆固醇和甘油三酯运输到整个身体的细胞外空间。含有载脂蛋白A-I和载脂蛋白E的小圆盘状脂蛋白在胆固醇逆向转运中起主要作用，这是一种将胆固醇从动脉粥样硬化病变中清除的机制。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x射线结晶学已经确定了apoA-I和apoE的无脂结构，但这两种载脂蛋白都缺乏与脂质相关的生理状态的详细结构信息。为了填补这一空白，我们结晶了模型apoA-I脂蛋白，它们活跃在胆固醇反向运输中，衍射率为20？，以及生理活性的apoE脂蛋白，衍射率为8？我们还在继续我们对无脂apoE的研究。最近的研究表明，脱脂apoE的COOH-末端结构域的细胞内裂解与阿尔茨海默病特有的细胞骨架破坏和神经细胞死亡类型有关。由于COOH-末端结构域的结构尚不清楚，我们正在测定有毒片段(残基223-272)的结构和完整的COOH-末端结构域，以了解该片段细胞毒性的结构基础。作为我们对载脂蛋白E感兴趣的结果，我们还研究了受体相关蛋白(RAP)的结构。RAP是低密度脂蛋白受体家族某些成员表达所必需的伴侣蛋白，也是低密度脂蛋白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.