Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Vic., Australia.
Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Vic., Australia.
FEBS J. 2018 Aug;285(15):2799-2812. doi: 10.1111/febs.14517. Epub 2018 Jun 9.
Human apolipoprotein (apo) C-II is one of several plasma apolipoproteins that form amyloid deposits in vivo and is an independent risk factor for cardiovascular disease. Lipid-free apoC-II readily self-assembles into twisted-ribbon amyloid fibrils but forms straight, rod-like amyloid fibrils in the presence of low concentrations of micellar phospholipids. Charge mutations exerted significantly different effects on rod-like fibril formation compared to their effects on twisted-ribbon fibril formation. For instance, the double mutant, K30D-D69K apoC-II, readily formed twisted-ribbon fibrils, while the rate of rod-like fibril formation in the presence of micellar phospholipid was negligible. Structural analysis of rod-like apoC-II fibrils, using hydrogen-deuterium exchange and NMR analysis showed exchange protection consistent with a core cross-β structure comprising the C-terminal 58-76 region. Molecular dynamics simulations of fibril arrangements for this region favoured a parallel cross-β structure. X-ray fibre diffraction data for aligned rod-like fibrils showed a major meridional spacing at 4.6 Å and equatorial spacings at 9.7, 23.8 and 46.6 Å. The latter two equatorial spacings are not observed for aligned twisted-ribbon fibrils and are predicted for a model involving two cross-β fibrils in an off-set antiparallel structure with four apoC-II units per rise of the β-sheet. This model is consistent with the mutational effects on rod-like apoC-II fibril formation. The lipid-dependent polymorphisms exhibited by apoC-II fibrils could determine the properties of apoC-II in renal amyloid deposits and their potential role in the development of cardiovascular disease.
人载脂蛋白（apo）C-II 是几种血浆载脂蛋白之一，可在体内形成淀粉样沉积物，是心血管疾病的独立危险因素。无脂 apoC-II 易于自组装成扭曲的带状淀粉样原纤维，但在低浓度胶束磷脂存在下形成直的、杆状的淀粉样原纤维。与对扭曲带状原纤维形成的影响相比，电荷突变对杆状原纤维形成的影响显著不同。例如，双突变体 K30D-D69K apoC-II 容易形成扭曲的带状原纤维，而在胶束磷脂存在下形成杆状原纤维的速率可以忽略不计。使用氢氘交换和 NMR 分析对杆状 apoC-II 原纤维的结构分析表明，交换保护与包含 C 端 58-76 区域的核心交叉-β 结构一致。该区域原纤维排列的分子动力学模拟有利于平行交叉-β 结构。对齐的杆状原纤维的 X 射线纤维衍射数据显示出 4.6 Å 的主要子午线间距和 9.7、23.8 和 46.6 Å 的赤道间距。后两个赤道间距在对齐的扭曲带状原纤维中观察不到，并且对于涉及两个交叉-β 原纤维的模型是预测的，该模型在交错的反平行结构中具有四个 apoC-II 单元/β-折叠的上升。该模型与对杆状 apoC-II 原纤维形成的突变影响一致。apoC-II 原纤维表现出的脂质依赖性多态性可以决定 apoC-II 在肾淀粉样沉积物中的特性及其在心血管疾病发展中的潜在作用。
