Molecular Insights into Human Hereditary Apolipoprotein A-I Amyloidosis Caused by the Glu34Lys Mutation.
Molecular Insights into Human Hereditary Apolipoprotein A-I Amyloidosis Caused by the Glu34Lys Mutation.
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Glu34Lys 突变引起的人类遗传性载脂蛋白 A-I 淀粉样变性的分子见解。
DOI：
10.1021/acs.biochem.8b00817
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发表时间：
2018
期刊：
影响因子：
2.9
通讯作者：
Gursky,Olga
中科院分区：
文献类型：
--
作者：
Morgado,Isabel;Panahi,Afra;Burwash,AndrewG;Das,Madhurima;Straub,JohnE;Gursky,Olga
遗传性载脂蛋白A-I（apoA-I）淀粉样变性是一种危及生命的不可治愈的遗传性疾病，其分子基础尚不清楚。在这种疾病中，变体apoA-I（高密度脂蛋白的主要结构和功能蛋白）以游离形式释放，经历α-螺旋到分子间交叉β-折叠的转化沿着蛋白水解裂解，并且作为淀粉样原纤维沉积在各种器官中，这可导致器官损伤和死亡。Glu 34 Lys是apoA-I中唯一已知的引起人类淀粉样变性的电荷倒置突变。为了阐明Glu 34 Lys apoA-I的淀粉样变性行为的结构基础，我们产生了其重组球状N-末端结构域（残基1-184），并将其无脂质形式的构象和动力学与其他两种天然存在的apoA-I变体Phe 71 Tyr（淀粉样变性）和Leu 159 Arg（非淀粉样变性）进行了比较。所有变体均显示结构稳定性降低和芳香残基堆积改变。在非淀粉样蛋白生成变体中观察到稳定性的最大降低，表明淀粉样蛋白形成是由敏感位点的局部结构扰动驱动的。分子动力学模拟揭示了当地的螺旋展开，并建议瞬时开放的Trp 72侧链诱导突变依赖的结构扰动的敏感区域，包括主要的淀粉样蛋白热点残基Leu 14-Leu 22。我们认为Trp 72侧链从“封闭”到“开放”方向的转变调节了淀粉样蛋白热点的结构保护，这表明蛋白质错误折叠途径中先前未知的早期步骤。
Hereditary apolipoprotein A-I (apoA-I) amyloidosis is a life-threatening incurable genetic disorder whose molecular underpinnings are unclear. In this disease, variant apoA-I, the major structural and functional protein of high-density lipoprotein, is released in a free form, undergoes an α-helix to intermolecular cross-β-sheet conversion along with a proteolytic cleavage, and is deposited as amyloid fibrils in various organs, which can cause organ damage and death. Glu34Lys is the only known charge inversion mutation in apoA-I that causes human amyloidosis. To elucidate the structural underpinnings of the amyloidogenic behavior of Glu34Lys apoA-I, we generated its recombinant globular N-terminal domain (residues 1–184) and compared the conformation and dynamics of its lipid-free form with those of two other naturally occurring apoA-I variants, Phe71Tyr (amyloidogenic) and Leu159Arg (non-amyloidogenic). All variants showed reduced structural stability and altered aromatic residue packing. The greatest decrease in stability was observed in the non-amyloidogenic variant, suggesting that amyloid formation is driven by local structural perturbations at sensitive sites. Molecular dynamics simulations revealed local helical unfolding and suggested that transient opening of the Trp72 side chain induced mutation-dependent structural perturbations in a sensitive region, including the major amyloid hot spot residues Leu14–Leu22. We posit that a shift from the “closed” to the “open” orientation of the Trp72 side chain modulates structural protection of amyloid hot spots, suggesting a previously unknown early step in the protein misfolding pathway.
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