THE STRUCTURE OF MODEL LIPOPROTEINS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 脂蛋白将胆固醇和甘油三酯转运到身体的整个细胞外空间。含有载脂蛋白A-I和载脂蛋白（apo）E的小圆盘形脂蛋白在胆固醇逆向转运中起主要作用，胆固醇通过这种机制从动脉粥样硬化病变中清除。含ApoE的脂蛋白也在神经元发育和修复期间的脂质转运中发挥关键作用。虽然载脂蛋白A-I和载脂蛋白E的无脂结构已被确定的X-射线晶体学，有一个缺乏详细的结构信息的载脂蛋白与脂质在其生理相关的状态。为了填补这一空白，我们结晶了模型apoA-I脂蛋白，它们在胆固醇逆向转运中具有活性，可作用于8，而生理活性apoE脂蛋白可作用于6。 我们还在继续研究无脂质apoE。无脂质载脂蛋白E的羧基末端结构域的细胞内裂解与细胞骨架破坏和阿尔茨海默病特征性神经元细胞死亡类型相关。的疾病。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的结构（残基222？272)和完整的COOH末端结构域，以了解片段的结构基础？细胞毒性。

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 8 ¿ and physiologically active apoE lipoproteins that diffract to 6 ¿. We are also continuing our studies of lipid-free apoE. 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 222?272) and the intact COOH-terminal domain in order to understand the structural basis of the fragment?s cellular toxicity.