On the lag phase in amyloid fibril formation.
On the lag phase in amyloid fibril formation.
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DOI：
10.1039/c4cp05563b
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发表时间：
2015-03-28
期刊：
影响因子：
--
通讯作者：
Linse S
中科院分区：
文献类型：
--
作者：
Arosio P;Knowles TP;Linse S
从a β42的初始单体4 μm溶液开始的反应，在淀粉样蛋白纤维形成滞后阶段发生的微观过程速率。正常可溶性多肽和蛋白质形成纳米级淀粉样蛋白原纤维是一种常见的自组装现象，与生物功能和人类疾病有着根本的联系。这一过程的动力学已被广泛研究，并在宏观水平上表现出三个特征阶段：滞后期、生长期和最终的平台期。在每一个阶段发生哪些分子事件的问题一直是寻求淀粉样蛋白形成机制的核心要素。在这篇综述中，我们利用物理化学，特别是化学反应动力学的工具和概念，讨论了淀粉样蛋白形成滞后期的性质和分子起源。我们讨论了在宏观样品中，滞后期显然不是原子核形成的等待时间。相反，存在多个平行过程，并且通常在溶液中的单体滞后阶段形成数百万个初生核。因此，滞后时间表示反应早期形成的细胞核生长和增殖所需的时间，以便达到易于在批量分析中检测到的聚集浓度。在许多情况下，这种增殖是通过二次成核发生的，其中原纤维可能为形成新的聚集体提供催化表面。原纤维也可能断裂（断裂），从而为伸长提供新的末端。因此，在滞后阶段至少发生两种初成核和延伸，在许多体系中至少发生四种初成核、延伸、二次成核和碎裂。此外，这些相同的过程发生在宏观聚集过程的所有三个阶段，尽管速率不同，但速率常数和每个时间点的反应物质浓度决定了这些过程。
Rates of microscopic processes taking place during the lag phase of amyloid fibril formation for a reaction starting from an initially monomeric 4 μm solution of Aβ42. The formation of nanoscale amyloid fibrils from normally soluble peptides and proteins is a common form of self-assembly phenomenon that has fundamental connections with biological functions and human diseases. The kinetics of this process has been widely studied and exhibits on a macroscopic level three characteristic stages: a lag phase, a growth phase and a final plateau regime. The question of which molecular events take place during each one of these phases has been a central element in the quest for a mechanism of amyloid formation. In this review, we discuss the nature and molecular origin of the lag-phase in amyloid formation by making use of tools and concepts from physical chemistry, in particular from chemical reaction kinetics. We discuss how, in macroscopic samples, it has become apparent that the lag-phase is not a waiting time for nuclei to form. Rather, multiple parallel processes exist and typically millions of primary nuclei form during the lag phase from monomers in solution. Thus, the lag-time represents a time that is required for the nuclei that are formed early on in the reaction to grow and proliferate in order to reach an aggregate concentration that is readily detected in bulk assays. In many cases, this proliferation takes place through secondary nucleation, where fibrils may present a catalytic surface for the formation of new aggregates. Fibrils may also break (fragmentation) and thereby provide new ends for elongation. Thus, at least two – primary nucleation and elongation – and in many systems at least four – primary nucleation, elongation, secondary nucleation and fragmentation – microscopic processes occur during the lag phase. Moreover, these same processes occur during all three phases of the macroscopic aggregation process, albeit at different rates as governed by rate constants and by the concentration of reacting species at each point in time.
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DOI：
10.1016/j.bbapap.2010.04.001
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
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