The ionization properties of cardiolipin and its variants in model bilayers.
The ionization properties of cardiolipin and its variants in model bilayers.
复制标题
DOI：
10.1016/j.bbamem.2016.03.007
复制
发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Alder NN
中科院分区：
文献类型：
--
作者：
Sathappa M;Alder NN
阴离子磷脂心磷脂具有一种特殊的二聚体结构，带有两个磷酸头基和四个酰基链。心磷脂存在于维持电化学梯度的能量转导膜中，包括大多数细菌质膜和线粒体内膜，在那里它介导呼吸复合体的组装和激活，以及许多其他作用。心磷脂的生物发生功能失调与包括Barth综合征在内的几种疾病的发病有关。由于心磷脂是节能膜中的主要阴离子脂类，其头部基团是表面电荷密度和双分子层静电分布的主要贡献者。然而，其头基的质子解离行为仍然存在争议。在一个模型中，磷酸盐的pKa值相差几个单位，头基在生理pH下以单一阴离子存在。在另一种模型中，两种磷酸盐都以低pKa值的强酸电离，头基在生理pH下以双阴离子形式存在。利用独立的电动和光谱方法，结合古伊-查普曼-斯特恩公式的分析，我们分析了生物相关的脂质双层模型体系中心磷脂的电离性质。我们发现心磷脂头基上的两种磷酸盐都表现出很强的电离行为，具有较低的pKa值。此外，缺乏结构特征的心磷脂变体被证明具有与完整心磷脂相同的电离行为，这些结构特征被认为是维持不同的PKA值所必需的--即中心甘油上的仲羟基或四个酰基链的完整补充。因此，这些结果表明，在生理pH范围内，心磷脂头部基团以阴离子的形式完全电离。我们讨论了这些结果对于心磷脂在确定膜表面电位、激活呼吸复合体和调节膜曲率方面的作用。
The anionic phospholipid cardiolipin has an unusual dimeric structure with a two-phosphate headgroup and four acyl chains. Cardiolipin is present in energy-transducing membranes that maintain electrochemical gradients, including most bacterial plasma membranes and the mitochondrial inner membrane, where it mediates respiratory complex assembly and activation, among many other roles. Dysfunctional biogenesis of cardiolipin is implicated in the pathogenesis of several diseases including Barth syndrome. Because cardiolipin is a dominant anionic lipid in energy-conserving membranes, its headgroup is a major contributor to surface charge density and the bilayer electrostatic profile. However, the proton dissociation behavior of its headgroup remains controversial. In one model, the pKa values of the phosphates differ by several units and the headgroup exists as a monoanion at physiological pH. In another model, both phosphates ionize as strong acids with low pKa values and the headgroup exists in dianionic form at physiological pH. Using independent electrokinetic and spectroscopic approaches, coupled with analysis using Gouy–Chapman–Stern formalism, we have analyzed the ionization properties of cardiolipin within biologically relevant lipid bilayer model systems. We show that both phosphates of the cardiolipin headgroup show strong ionization behavior with low pKa values. Moreover, cardiolipin variants lacking structural features proposed to be required to maintain disparate pKa values – namely the secondary hydroxyl on the central glycerol or a full complement of four acyl chains – were shown to have ionization behavior identical to intact cardiolipin. Hence, these results indicate that within the physiological pH range, the cardiolipin headgroup is fully ionized as a dianion. We discuss the implications of these results with respect to the role of cardiolipin in defining membrane surface potential, activating respiratory complexes, and modulating membrane curvature.