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首页> 外文期刊>Journal of Molecular Biology >Apolipoprotein C-II amyloid fibrils assemble via a reversible pathway that includes fibril breaking and rejoining
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Apolipoprotein C-II amyloid fibrils assemble via a reversible pathway that includes fibril breaking and rejoining

机译：载脂蛋白C-II淀粉样蛋白原纤维通过可逆途径组装，包括原纤维断裂和重新结合

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Alzheimer's and several other diseases are characterized by the misfolding and assembly of protein subunits into amyloid fibrils. Current models propose that amyloid fibril formation proceeds via the self-association of several monomers to form a nucleus, which then elongates by the addition of monomer to form mature fibrils. We have examined the concentration-dependent kinetics of apolipoprotein C-II amyloid fibril formation and correlated this with the final size distribution of the fibrils determined by sedimentation velocity experiments. In contrast to predictions of the nucleation-elongation model, the final size distribution of the fibrils was found to be relatively independent of the starting monomer concentration. To explain these results, we extended the nucleation-elongation model to include fibril breaking and rejoining as integral parts of the amyloid fibril assembly mechanism. The system was examined under conditions that affected the stability of the mature fibrils, including the effect of dilution on the free pool of monomeric apolipoprotein C-II and the time-dependent recovery of fibril size following sonication. Antibody-labelling transmission electron microscopy studies provided direct evidence for spontaneous fibril breaking and rejoining. These studies establish the importance of breaking and rejoining in amyloid fibril formation and identify prospective new therapeutic targets in the assembly pathway. (C) 2008 Elsevier Ltd. All rights reserved.
机译：阿尔茨海默氏病和其他几种疾病的特征是蛋白质亚基错误折叠和组装成淀粉样蛋白原纤维。当前模型提出淀粉状蛋白原纤维的形成通过几种单体的自缔合形成核，然后通过加入单体而伸长形成成熟的原纤维。我们已经检查了载脂蛋白C-II淀粉样蛋白原纤维形成的浓度依赖性动力学，并将其与通过沉降速度实验确定的原纤维的最终尺寸分布相关。与成核-伸长模型的预测相反，发现原纤维的最终尺寸分布相对独立于起始单体浓度。为了解释这些结果，我们扩展了成核-伸长模型，将原纤维的断裂和重新结合作为淀粉样蛋白原纤维组装机制的组成部分。在影响成熟纤丝稳定性的条件下检查了该系统，包括稀释对单体载脂蛋白C-II游离池的影响以及超声处理后纤丝尺寸随时间的恢复。抗体标记的透射电子显微镜研究提供了自发性原纤维断裂和重新结合的直接证据。这些研究确立了破坏和重新结合淀粉样蛋白原纤维形成的重要性，并确定了组装途径中潜在的新治疗靶标。 （C）2008 Elsevier Ltd.保留所有权利。

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