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A Targeted, Differential Top-Down Proteomic Methodology for Comparison of ApoA-I Proteoforms in Individuals with High and Low HDL Efflux Capacity
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2018-04-27 , DOI: 10.1021/acs.jproteome.8b00100
Henrique Dos Santos Seckler , Luca Fornelli , R Kannan Mutharasan 1 , C Shad Thaxton , Ryan Fellers , Martha Daviglus 2 , Allan Sniderman 3 , Daniel Rader , Neil L Kelleher , Donald M Lloyd-Jones 1 , Philip D Compton , John T Wilkins 1
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Top-down proteomics (TDP) allows precise determination/characterization of the different proteoforms derived from the expression of a single gene. In this study, we targeted apolipoprotein A-I (ApoA-I), a mediator of high-density-lipoprotein cholesterol efflux (HDL-E), which is inversely associated with coronary heart disease risk. Absolute ApoA-I concentration and allelic variation only partially explain interindividual HDL-E variation. Therefore, we hypothesize that differences in HDL-E are associated with the abundances of different ApoA-I proteoforms. Here, we present a targeted TDP methodology to characterize ApoA-I proteoforms in serum samples and compare their abundances between individuals. We characterized 18 ApoA-I proteoforms using selected-ion monitoring coupled to electron-transfer dissociation mass spectrometry. We then compared the abundances of these proteoforms between two groups of four participants, representing the individuals with highest and lowest HDL-E values within the Chicago Healthy Aging Study (n = 420). Six proteoforms showed significantly (p < 0.0005) higher intensity in high HDL-E individuals: canonical ApoA-I [fold difference (fd) = 1.17], carboxymethylated ApoA-I (fd = 1.24) and, with highest difference, four fatty acylated forms: palmitoylated (fd = 2.16), oleoylated (fd = 2.08), arachidonoylated (fd = 2.31) and one bearing two modifications: palmitoylation and truncation (fd = 2.13). These results demonstrate translational potential for targeted TDP in revealing, with high sensitivity, associations between interindividual proteoform variation and physiological differences underlying disease risk.

中文翻译:


一种有针对性、差异化的自上而下蛋白质组学方法,用于比较具有高和低 HDL 流出能力的个体中的 ApoA-I 蛋白质组



自上而下的蛋白质组学 (TDP) 可以精确测定/表征源自单个基因表达的不同蛋白质形式。在这项研究中,我们的目标是载脂蛋白 AI (ApoA-I),它是高密度脂蛋白胆固醇流出 (HDL-E) 的介质,与冠心病风险呈负相关。绝对 ApoA-I 浓度和等位基因变异只能部分解释个体间 HDL-E 变异。因此,我们假设 HDL-E 的差异与不同 ApoA-I 蛋白异构体的丰度相关。在这里,我们提出了一种有针对性的 TDP 方法来表征血清样本中的 ApoA-I 蛋白质形式并比较其在个体之间的丰度。我们使用选择离子监测与电子转移解离质谱联用对 18 种 ApoA-I 蛋白异构体进行了表征。然后,我们比较了两组四名参与者之间这些蛋白质形式的丰度,这些参与者代表了芝加哥健康老龄化研究中 HDL-E 值最高和最低的个体( n = 420)。六种蛋白质形式在高 HDL-E 个体中表现出显着更高的强度 ( p < 0.0005):典型 ApoA-I [倍数差异 (fd) = 1.17]、羧甲基化 ApoA-I (fd = 1.24) 以及差异最高的四种脂肪酰化蛋白形式:棕榈酰化(fd = 2.16)、油酰化(fd = 2.08)、花生四烯酰化(fd = 2.31)以及一种具有两种修饰的形式:棕榈酰化和截短(fd = 2.13)。这些结果证明了靶向 TDP 的转化潜力,可以高灵敏度地揭示个体间蛋白质变异与潜在疾病风险的生理差异之间的关联。
更新日期:2018-04-28
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