Structural Basis for the Recognition of Oxidized Phospholipids in Oxidized Low Density Lipoproteins by Class B Scavenger Receptors CD36 and SR-BI
Structural Basis for the Recognition of Oxidized Phospholipids in Oxidized Low Density Lipoproteins by Class B Scavenger Receptors CD36 and SR-BI
复制标题
DOI：
10.1074/jbc.m109.082800
复制
发表时间：
2010-02-12
影响因子：
4.8
通讯作者：
Podrez, Eugene A.
中科院分区：
文献类型：
--
作者：
Gao, Detao;Ashraf, Mohammad Z.;Podrez, Eugene A.
特异性氧化磷脂（oxPC（CD 36））在体内氧化应激部位蓄积，并作为清道夫受体B类（CD 36和SR-BI）的高亲和力配体。清道夫受体对oxPC（CD 36）的识别在多种病理生理过程中发挥作用。CD 36和SR-BI识别oxPC（CD 36）的结构基础知之甚少。oxPC（CD 36）的一个典型特征是一个sn-2酰基，它包含一个末端γ-羟基（或氧代）-α，β-不饱和羰基。在本研究中，设计、合成了一系列模型氧化磷脂，并测试了它们作为CD 36和SR-BI配体的能力。我们证明，完整的sn-1疏水链，sn-3亲水磷酸胆碱或磷脂酸基团，和极性的sn-2尾巴是绝对必要的高亲和力结合。我们进一步发现，在sn-2位的末端带负电荷的羧酸盐足以产生对B类清道夫受体的高结合亲和力。此外，诸如极性、刚性、sn-2和sn-3位置的最佳链长以及磷脂的sn-3位置处的负电荷等因素进一步调节结合亲和力。我们的结论是，所有三个位置的氧化磷脂是必不可少的清道夫受体类B的有效识别。此外，这些位置中残基的结构控制结合的亲和力。目前的研究表明，除了oxPC（CD 36）之外，体内观察到的其他氧化磷脂可能代表了B类清道夫受体的新型配体。
Specific oxidized phospholipids (oxPC(CD36)) accumulate in vivo at sites of oxidative stress and serve as high affinity ligands for scavenger receptors class B (CD36 and SR-BI). Recognition of oxPC(CD36) by scavenger receptors plays a role in several pathophysiological processes. The structural basis for the recognition of oxPC(CD36) by CD36 and SR-BI is poorly understood. A characteristic feature of oxPC(CD36) is an sn-2 acyl group that incorporates a terminal gamma-hydroxy (or oxo)-alpha,beta-unsaturated carbonyl. In the present study, a series of model oxidized phospholipids were designed, synthesized, and tested for their ability to serve as ligands for CD36 and SR-BI. We demonstrated that intact the sn-1 hydrophobic chain, the sn-3 hydrophilic phosphocholine or phosphatidic acid group, and the polar sn-2 tail are absolutely essential for high affinity binding. We further found that a terminal negatively charged carboxylate at the sn-2 position suffices to generate high binding affinity to class B scavenger receptors. In addition, factors such as polarity, rigidity, optimal chain length of sn-2, and sn-3 positions and negative charge at the sn-3 position of phospholipids further modulate the binding affinity. We conclude that all three positions of oxidized phospholipids are essential for the effective recognition by scavenger receptors class B. Furthermore, the structure of residues in these positions controls the affinity of the binding. The present studies suggest that, in addition to oxPC(CD36), other oxidized phospholipids observed in vivo may represent novel ligands for scavenger receptors class B.