Effects of Disease-Causing Mutations on the Conformation of Human Apolipoprotein A-I in Model Lipoproteins,Biochemistry

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Effects of Disease-Causing Mutations on the Conformation of Human Apolipoprotein A-I in Model Lipoproteins
Biochemistry ( IF 2.9 ) Pub Date : 2018-07-13 00:00:00 , DOI: 10.1021/acs.biochem.8b00538
Christopher J. Wilson ₁ , Madhurima Das ₂ , Shobini Jayaraman ₂ , Olga Gursky _{2,

3} , John R. Engen ₁

Affiliation

Plasma high-density lipoproteins (HDLs) are protein–lipid nanoparticles that transport lipids and protect against atherosclerosis. Human apolipoprotein A-I (apoA-I) is the principal HDL protein whose mutations can cause either aberrant lipid metabolism or amyloid disease. Hydrogen–deuterium exchange (HDX) mass spectrometry (MS) was used to study the apoA-I conformation in model discoidal lipoproteins similar in size to large plasma HDL. We examined how point mutations associated with hereditary amyloidosis (F71Y and L170P) or atherosclerosis (L159R) influence the local apoA-I conformation in model lipoproteins. Unlike other apoA-I forms, the large particles showed minimal conformational heterogeneity, suggesting a fully extended protein conformation. Mutation-induced structural perturbations in lipid-bound protein were attenuated compared to the free protein and indicated close coupling between the two belt-forming apoA-I molecules. These perturbations propagated to distant lipoprotein sites, either increasing or decreasing their protection. This HDX MS study of large model HDL, compared with previous studies of smaller particles, ascertained that apoA-I’s central region helps accommodate the protein conformation to lipoproteins of various sizes. This study also reveals that the effects of mutations on lipoprotein conformational dynamics are much weaker than those in a lipid-free protein. Interestingly, the mutation-induced perturbations propagate to distant sites nearly 10 nm away and alter their protection in ways that cannot be predicted from the lipoprotein structure and stability. We propose that long-range mutational effects are mediated by both protein and lipid and can influence lipoprotein functionality.

中文翻译：

致病突变对模型脂蛋白中人类载脂蛋白AI构象的影响

血浆高密度脂蛋白（HDL）是蛋白质脂质纳米颗粒，可转运脂质并防止动脉粥样硬化。人类载脂蛋白AI（apoA-I）是主要的HDL蛋白，其突变可能导致异常的脂质代谢或淀粉样蛋白疾病。氢氘交换（HDX）质谱（MS）用于研究模型盘状脂蛋白中apoA-I的构型，其大小与大血浆HDL相似。我们检查了与遗传性淀粉样变性病（F71Y和L170P）或动脉粥样硬化（L159R）相关的点突变如何影响模型脂蛋白中的局部apoA-I构象。与其他apoA-I形式不同，大颗粒显示出最小的构象异质性，表明蛋白质构象已完全扩展。与游离蛋白相比，脂质结合蛋白中的突变诱导的结构扰动被减弱，并且表明两个形成带的载脂蛋白A-1分子之间的紧密偶联。这些扰动传播到遥远的脂蛋白部位，从而增加或降低了它们的保护作用。与先前对较小颗粒的研究相比，该对HDL大型模型的HDX MS研究确定了apoA-I的中央区域有助于适应各种大小的脂蛋白的蛋白质构象。这项研究还表明，突变对脂蛋白构象动力学的影响远弱于无脂蛋白。有趣的是，由突变引起的扰动传播到近10 nm处的远处，并以脂蛋白结构和稳定性无法预测的方式改变对它们的保护。

更新日期：2018-07-13

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