Anantharamaiah G M, Mishra Vinod K, Garber David W, Datta Geeta, Handattu Shaila P, Palgunachari Mayakonda N, Chaddha Manjula, Navab Mohamad, Reddy Srinivasa T, Segrest Jere P, Fogelman Alan M
Department of Medicine, Biochemistry, and Molecular Genetics and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
J Lipid Res. 2007 Sep;48(9):1915-23. doi: 10.1194/jlr.R700010-JLR200. Epub 2007 Jun 14.
Recently, attention has been focused on pharmacological treatments that increase HDL cholesterol to prevent coronary artery disease. Despite three decades of extensive research of human apolipoprotein A-I (apoA-I), the major protein component of HDL, the molecular basis for its antiatherogenic and anti-inflammatory functions remain elusive. Another protein component of HDL, apoA-II, has structural features similar to those of apoA-I but does not possess atheroprotective properties. To understand the molecular basis for the effectiveness of apoA-I, we used model synthetic peptides. We designed analogs of the class A amphipathic helical motif in apoA-I that is responsible for solubilizing phospholipids. None of these analogs has sequence homology to apoA-I, but all are similar in their lipid-associating structural motifs. Although all of these peptide analogs interact with phospholipids to form peptide:lipid complexes, the biological properties of these analogs are different. Physical-chemical and NMR studies of these peptides have enabled the delineation of structural requirements for atheroprotective and anti-inflammatory properties in these peptides. It has been shown that peptides that interact strongly with lipid acyl chains do not have antiatherogenic and anti-inflammatory properties. In contrast, peptides that associate close to the lipid head group (and hence do not interact strongly with the lipid acyl chain) are antiatherogenic and anti-inflammatory. Understanding the structure and function of apoA-I and HDL through studies of the amphipathic helix motif may lead to peptide-based therapies for inhibiting atherosclerosis and other related inflammatory lipid disorders.
最近，注意力集中在通过增加高密度脂蛋白胆固醇来预防冠状动脉疾病的药物治疗上。尽管对高密度脂蛋白的主要蛋白质成分人类载脂蛋白A-I（apoA-I）进行了三十年的广泛研究，但其抗动脉粥样硬化和抗炎功能的分子基础仍然难以捉摸。高密度脂蛋白的另一种蛋白质成分载脂蛋白A-II，具有与apoA-I相似的结构特征，但不具备抗动脉粥样硬化特性。为了理解apoA-I有效性的分子基础，我们使用了模型合成肽。我们设计了apoA-I中负责溶解磷脂的A类两亲性螺旋基序的类似物。这些类似物中没有一个与apoA-I具有序列同源性，但它们在脂质结合结构基序方面都很相似。尽管所有这些肽类似物都与磷脂相互作用形成肽：脂质复合物，但这些类似物的生物学特性却有所不同。对这些肽的物理化学和核磁共振研究使得能够描绘出这些肽中抗动脉粥样硬化和抗炎特性的结构要求。已经表明，与脂质酰基链强烈相互作用的肽不具有抗动脉粥样硬化和抗炎特性。相反，与脂质头部基团紧密结合（因此与脂质酰基链没有强烈相互作用）的肽具有抗动脉粥样硬化和抗炎作用。通过对两亲性螺旋基序的研究来理解apoA-I和高密度脂蛋白的结构与功能，可能会导致基于肽的疗法来抑制动脉粥样硬化和其他相关的炎症性脂质紊乱。
