Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia.
Network. 2011;22(1-4):154-61. doi: 10.3109/0954898X.2011.639842.
Neurodegenerative diseases present a big burden to society. At the molecular level many of them - if not all - show protein aggregation (as an epiphenomenon or as a cause). The knowledge on details of thermodynamics and kinetics as well as structure of the protein aggregates, especially the early and soluble oligomers, may help in designing inhibitors for early stages of such diseases. Here, a possible outlook on more general mechanism for their formation is discussed. The oligomers of amyloid forming proteins, which are present prior and during nucleation and amyloid fibril formation, are claimed to be toxic to cells. Oligomers of the globular proteins and the intrinsically disordered proteins (IDPs), form in vitro upon partial denaturation and renaturation, respectively. Often they form if the sample is heated or freeze-thawed for a few cycles. A question is asked if this does not highlight one important property in common to globular proteins and IDPs, namely, a high energetic barrier dividing such oligomers from the monomers. This also would imply existence of two populations of states, one, the monomer - being metastable - at least under the conditions, which promote fibril formation.
神经退行性疾病给社会带来了巨大负担。在分子水平上，它们中的许多疾病——如果不是全部的话——都表现出蛋白质聚集（作为一种伴随现象或原因）。对蛋白质聚集物的热力学和动力学细节以及结构的了解，特别是早期可溶性低聚物，可能有助于设计针对这些疾病早期阶段的抑制剂。在这里，讨论了一种形成它们的更普遍机制的可能前景。在核形成和淀粉样纤维形成之前和期间存在的淀粉样蛋白形成蛋白的低聚物被认为对细胞有毒。球状蛋白和固有无序蛋白（IDP）的低聚物分别在部分变性和复性时形成。通常，如果样品加热或反复冷冻解冻几次，它们就会形成。人们不禁要问，如果这不能突出球状蛋白和 IDP 之间的一个共同重要性质，即从单体到低聚物的高能量障碍。这也意味着存在两种状态群体，一种是单体——至少在促进纤维形成的条件下处于亚稳定状态。
