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Origin of metastable oligomers and their effects on amyloid fibril self-assembly†
Chemical Science ( IF 8.4 ) Pub Date : 2018-06-13 00:00:00 , DOI: 10.1039/c8sc01479e
Filip Hasecke 1, 2, 3, 4 , Tatiana Miti 5, 6, 7, 8 , Carlos Perez 5, 6, 7, 8 , Jeremy Barton 5, 6, 7, 8 , Daniel Schölzel 1, 2, 3, 4, 9 , Lothar Gremer 1, 2, 3, 4, 9 , Clara S. R. Grüning 1, 2, 3, 4 , Garrett Matthews 5, 6, 7, 8 , Georg Meisl 10, 11, 12, 13 , Tuomas P. J. Knowles 10, 11, 12, 13 , Dieter Willbold 1, 2, 3, 4, 9 , Philipp Neudecker 1, 2, 3, 4, 9 , Henrike Heise 1, 2, 3, 4, 9 , Ghanim Ullah 5, 6, 7, 8 , Wolfgang Hoyer 1, 2, 3, 4, 9 , Martin Muschol 5, 6, 7, 8
Affiliation  

Assembly of rigid amyloid fibrils with their characteristic cross-β sheet structure is a molecular signature of numerous neurodegenerative and non-neuropathic disorders. Frequently large populations of small globular amyloid oligomers (gOs) and curvilinear fibrils (CFs) precede the formation of late-stage rigid fibrils (RFs), and have been implicated in amyloid toxicity. Yet our understanding of the origin of these metastable oligomers, their role as on-pathway precursors or off-pathway competitors, and their effects on the self-assembly of amyloid fibrils remains incomplete. Using two unrelated amyloid proteins, amyloid-β and lysozyme, we find that gO/CF formation, analogous to micelle formation by surfactants, is delineated by a “critical oligomer concentration” (COC). Below this COC, fibril assembly replicates the sigmoidal kinetics of nucleated polymerization. Upon crossing the COC, assembly kinetics becomes biphasic with gO/CF formation responsible for the lag-free initial phase, followed by a second upswing dominated by RF nucleation and growth. RF lag periods below the COC, as expected, decrease as a power law in monomer concentration. Surprisingly, the build-up of gO/CFs above the COC causes a progressive increase in RF lag periods. Our results suggest that metastable gO/CFs are off-pathway from RF formation, confined by a condition-dependent COC that is distinct from RF solubility, underlie a transition from sigmoidal to biphasic assembly kinetics and, most importantly, not only compete with RFs for the shared monomeric growth substrate but actively inhibit their nucleation and growth.

中文翻译:

亚稳态低聚物的起源及其对淀粉样蛋白原纤维自组装的影响

具有特征性交叉β折叠结构的刚性淀粉样蛋白原纤维的组装是许多神经退行性疾病和非神经性疾病的分子特征。小球状淀粉样蛋白低聚物(gOs)和曲线原纤维(CFs)经常大量出现在后期刚性原纤维(RFs)形成之前,并且与淀粉样蛋白毒性有关。然而,我们对这些亚稳态低聚物的起源,它们作为通路前体或通路竞争者的作用以及它们对淀粉样原纤维自组装的影响的理解仍然不完整。使用两种不相关的淀粉样蛋白,淀粉样蛋白-β和溶菌酶,我们发现gO / CF的形成类似于表面活性剂的胶束形成,由“临界低聚物浓度”(COC)来描述。在此COC以下,原纤维组装复制了成核聚合的S形动力学。越过COC,组装动力学就变成双相的,其中gO / CF的形成负责无滞后的初始阶段,然后是RF成核和生长为主的第二次上升。如预期的那样,低于COC的RF滞后周期随单体浓度的幂律而减小。令人惊讶的是,COO上方的gO / CF积聚导致RF滞后周期逐渐增加。我们的结果表明,亚稳态gO / CFs偏离了RF的形成,受到与RF溶解度不同的条件依赖性COC的限制,是从S形到双相组装动力学的过渡,而且最重要的是,不仅与RFs竞争共享的单体生长底物,但积极抑制其成核和生长。越过COC,组装动力学就变成双相的,其中gO / CF的形成负责无滞后的初始阶段,然后是RF成核和生长为主的第二次上升。如预期的那样,低于COC的RF滞后周期随单体浓度的幂律而减小。令人惊讶的是,COO上方的gO / CF积聚导致RF滞后周期逐渐增加。我们的结果表明,亚稳态gO / CFs偏离了RF的形成,受到与RF溶解度不同的条件依赖性COC的限制,是从S形到双相组装动力学的过渡,而且最重要的是,不仅与RFs竞争共享的单体生长底物,但积极抑制其成核和生长。越过COC,组装动力学就变成双相的,其中gO / CF的形成负责无滞后的初始阶段,然后是RF成核和生长为主的第二次上升。如预期的那样,低于COC的RF滞后周期随单体浓度的幂律而减小。令人惊讶的是,COO上方的gO / CF积聚导致RF滞后周期逐渐增加。我们的结果表明,亚稳态gO / CFs偏离了RF的形成,受到与RF溶解度不同的条件依赖性COC的限制,是从S形到双相组装动力学的过渡,而且最重要的是,不仅与RFs竞争共享的单体生长底物,但积极抑制其成核和生长。随后是第二次上升,主要由射频成核和生长引起。如预期的那样,低于COC的RF滞后周期随单体浓度的幂律而减小。令人惊讶的是,COO上方的gO / CF积聚导致RF滞后周期逐渐增加。我们的结果表明,亚稳态gO / CFs偏离了RF的形成,受到与RF溶解度不同的条件依赖性COC的限制,是从S形到双相组装动力学的过渡,而且最重要的是,不仅与RFs竞争共享的单体生长底物,但积极抑制其成核和生长。随后是第二次上升,主要由射频成核和生长引起。如预期的那样,低于COC的RF滞后周期随单体浓度的幂律而减小。令人惊讶的是,COC上方的gO / CF积聚导致RF滞后周期逐渐增加。我们的结果表明,亚稳态gO / CFs偏离了RF的形成,受到与RF溶解度不同的条件依赖性COC的限制,是从S形到双相组装动力学的过渡,而且最重要的是,不仅与RFs竞争共享的单体生长底物,但积极抑制其成核和生长。gO / CF在COC之上的堆积会导致RF滞后周期的逐渐增加。我们的结果表明,亚稳态gO / CFs偏离了RF的形成,受到与RF溶解度不同的条件依赖性COC的限制,是从S形到双相组装动力学的过渡,而且最重要的是,不仅与RFs竞争共享的单体生长底物,但积极抑制其成核和生长。gO / CF在COC之上的堆积会导致RF滞后周期的逐渐增加。我们的结果表明,亚稳态gO / CFs偏离了RF的形成,受到与RF溶解度不同的条件依赖性COC的限制,是从S形到双相组装动力学的过渡,而且最重要的是,不仅与RFs竞争共享的单体生长底物,但积极抑制其成核和生长。
更新日期:2018-06-13
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