APOLIPOPROTEIN E AND A 1 LIPID COMPLEX STRUCTURES

载脂蛋白(Apo)E和apoA-1在细胞周期调控和细胞周期调控中发挥重要作用。 指导血浆脂蛋白代谢。任何一种蛋白质的功能障碍都会导致动脉粥样硬化增加，最终导致心脏病和中风。此外，apoE4是一种 已确定的神经退行性变和颅脑损伤预后不良的危险因素 还有中风。尽管载脂蛋白E和载脂蛋白A-1在正常生理中起着关键作用， 这些蛋白质中的任何一种都没有详细的结构信息 天然的脂质结合状态。这一建议是基于我们最近在结晶载脂蛋白-磷脂复合体方面的技术突破，旨在首次提供载脂蛋白E和载脂蛋白A-I与脂质结合的详细结构信息。三个具体目标侧重于与载脂蛋白E和载脂蛋白A-I的结构和功能有关的问题和问题。 1.载脂蛋白E-二肉豆蔻基磷脂酰胆碱(DMPC)络合物的结构 确定脂质结合如何影响载脂蛋白E功能。 2.假设apoA-1采用所谓的“带模式”构象。 将对磷脂圆盘进行测试，并了解其相互作用的结构细节 具有脂质和对LCAT激活的洞察的apoA-1两亲性螺旋将是 如果是这样的话。 3.分析胆固醇掺入磷脂的影响 ApoE和apoA-1结构上的盘状颗粒。 这些研究将为脂质的作用提供新的结构信息。 载脂蛋白E和载脂蛋白A-1的结构和功能的联系，并为 第一次，洞察这些蛋白质如何在其天然的 脂质相关状态。

Apolipoprotein (apo) E and apoA-1 play several critical roles in modulating and in directing plasma lipoprotein metabolism. Dysfunction by either protein leads to increased atherosclerosis and ultimately to heart disease and stroke. In addition, apoE4 is an established risk factor for neurodegeneration and poor outcome from head injury and stroke. Despite the critical roles that apoE and apoA-1 play in normal physiology, detailed structural information is not available for either of these proteins in their natural lipid-bound state. This proposal is based on our recent technological breakthrough of crystalling apolipoprotein-phospholipid complexes and is designed to provide, for the first time, detailed structural information on apoE and apoA-I bound to lipid. Three specific aims focus on relevant issues and questions related to the structure and function of apoE and apoA-I. 1. The structures of apoE-dimyristoylphosphatidylcholine (DMPC) complexes will be determined to ascertain how lipid association influences apoE function. 2. The hypothesis that apoA-1 adopts the so-called "belt model" conformation on a phospholipid disc will be tested and structural details on the interaction of apoA-1 amphipathic helices with lipid and insights into LCAT activation will be provided. 3. To analyze the effect of cholesterol incorporation into phospholipid discoidal particles on the structure of apoE and apoA-1. These studies will provide novel structural information on the effect of lipid association on the structure and function of apoE and apoA-1 and provide, for the first time, insights into how these proteins function in their natural lipid-associated state.