Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development.
Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development.
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DOI：
10.1016/j.arcmed.2015.05.012
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发表时间：
2015-07
影响因子：
7.7
通讯作者：
Atkinson D
中科院分区：
文献类型：
--
作者：
Mei X;Atkinson D
载脂蛋白A-I是高密度脂蛋白（HDL）中的主要蛋白质，在胆固醇逆向转运（RCT）过程中起重要作用。全长apoA-I的高分辨率结构的知识是至关重要的分子HDL的RCT途径的各个步骤的功能的理解。由于apoA-I的柔性性质和聚集性质，全长无脂质apoA-I的结构已经回避了三十多年的描述。apoA-I的序列分析表明，两亲性α-螺旋是可交换载脂蛋白的结构基序，NMR、X射线和分子动力学模拟研究证实了这一点。不同的实验室已经使用不同的方法来探测二级结构分布和无脂质和脂质结合的apoA-I结构的组织。突变分析、合成肽模型、表面化学和晶体结构已集中在无脂质apoA-I结构域的结构和功能上：N-末端结构域[1-184]形成螺旋束，而C-末端结构域[185-243]大多缺乏确定的结构，负责启动脂质结合、聚集，也参与胆固醇流出。apoA-I的前43个残基对于稳定无脂质结构是必不可少的。此外，C-末端截短的apoA-I的晶体结构表明HDL形成过程中通过螺旋5重组和二聚化介导的单体-二聚体转化机制。在前人研究的基础上，我们提出了全长单体apoA-I在溶液中的结构模型，并通过三个中间状态更新了HDL的形成机制。在全长单体apoA-I模型上绘制已知的自然突变，通过破坏N-末端螺旋束或缺失C-末端脂质结合结构域，提供了对动脉粥样硬化发展的深入了解。
Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT). Knowledge of the high-resolution structure of full-length apoA-I is vital for a molecular understanding of the function of HDL at the various steps of the RCT pathway. Due to the flexible nature of apoA-I and aggregation properties, the structure of full-length lipid-free apoA-I has evaded description for over three decades. Sequence analysis of apoA-I suggested that the amphipathic α-helix is the structural motif of exchangeable apolipoprotein, and NMR, X-ray and MD simulation studies have confirmed this. Different laboratories have used different methods to probe the secondary structure distribution and organization of both the lipid-free and lipid-bound apoA-I structure. Mutation analysis, synthetic peptide models, surface chemistry and crystal structures have converged on the lipid-free apoA-I domain structure and function: the N-terminal domain [1–184] forms a helix bundle while the C-terminal domain [185–243] mostly lacks defined structure and is responsible for initiating lipid-binding, aggregation and is also involved in cholesterol efflux. The first 43 residues of apoA-I are essential to stabilize the lipid-free structure. In addition, the crystal structure of C-terminally truncated apoA-I suggests a monomer-dimer conversation mechanism mediated through helix 5 reorganization and dimerization during the formation of HDL. Based on previous research, we have proposed a structural model for full-length monomeric apoA-I in solution and updated the HDL formation mechanism through three intermediate states. Mapping the known natural mutations on the full-length monomeric apoA-I model provides insight into atherosclerosis development through disruption of the N-terminal helix bundle or deletion of the C-terminal lipid-binding domain.