Chiti Fabrizio, Dobson Christopher M
Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, I-50134 Firenze, Italy.
Nat Chem Biol. 2009 Jan;5(1):15-22. doi: 10.1038/nchembio.131.
The conversion of proteins from their soluble states into well-organized fibrillar aggregates is associated with a wide range of pathological conditions, including neurodegenerative diseases and systemic amyloidoses. In this review, we discuss the mechanism of aggregation of globular proteins under conditions in which they are initially folded. Although a conformational change of the native state is generally necessary to initiate aggregation, we show that a transition across the major energy barrier for unfolding is not essential and that aggregation may well be initiated from locally unfolded states that become accessible, for example, via thermal fluctuations occurring under physiological conditions. We review recent evidence on this topic and discuss its significance for understanding the onset and potential inhibition of protein aggregation in the context of diseases.
蛋白质从可溶状态转变为有序的纤维状聚集体与多种病理状况相关，包括神经退行性疾病和全身性淀粉样变性。在本综述中，我们讨论了球状蛋白质在其最初折叠状态下的聚集机制。虽然天然状态的构象变化通常是引发聚集所必需的，但我们表明跨越主要的解折叠能量屏障并非是必不可少的，而且聚集很可能是从例如通过生理条件下发生的热涨落而变得可及的局部解折叠状态开始的。我们综述了关于这一主题的最新证据，并讨论了其对于理解疾病背景下蛋白质聚集的起始及潜在抑制的意义。
