Wright Maya A, Aprile Francesco A, Arosio Paolo, Vendruscolo Michele, Dobson Christopher M, Knowles Tuomas P J
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Chem Commun (Camb). 2015 Oct 4;51(77):14425-34. doi: 10.1039/c5cc03689e.
Molecular chaperones are key components of the arsenal of cellular defence mechanisms active against protein aggregation. In addition to their established role in assisting protein folding, increasing evidence indicates that molecular chaperones are able to protect against a range of potentially damaging aspects of protein behaviour, including misfolding and aggregation events that can result in the generation of aberrant protein assemblies whose formation is implicated in the onset and progression of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The interactions between molecular chaperones and different amyloidogenic protein species are difficult to study owing to the inherent heterogeneity of the aggregation process as well as the dynamic nature of molecular chaperones under physiological conditions. As a consequence, understanding the detailed microscopic mechanisms underlying the nature and means of inhibition of aggregate formation remains challenging yet is a key objective for protein biophysics. In this review, we discuss recent results from biophysical studies on the interactions between molecular chaperones and protein aggregates. In particular, we focus on the insights gained from current experimental techniques into the dynamics of the oligomerisation process of molecular chaperones, and highlight the opportunities that future biophysical approaches have in advancing our understanding of the great variety of biological functions of this important class of proteins.
分子伴侣是细胞防御机制中对抗蛋白质聚集的关键组成部分。除了在协助蛋白质折叠方面已确立的作用外，越来越多的证据表明，分子伴侣能够抵御蛋白质行为的一系列潜在有害方面，包括错误折叠和聚集事件，这些事件可能导致异常蛋白质聚集体的产生，其形成与神经退行性疾病（如阿尔茨海默病和帕金森病）的发生和发展有关。由于聚集过程固有的异质性以及分子伴侣在生理条件下的动态性质，分子伴侣与不同淀粉样蛋白物种之间的相互作用难以研究。因此，了解抑制聚集体形成的本质和方式背后的详细微观机制仍然具有挑战性，但这是蛋白质生物物理学的一个关键目标。在这篇综述中，我们讨论了关于分子伴侣与蛋白质聚集体相互作用的生物物理研究的最新结果。特别是，我们关注从当前实验技术中获得的关于分子伴侣寡聚化过程动力学的见解，并强调未来生物物理方法在推进我们对这类重要蛋白质的多种生物学功能的理解方面所具有的机会。
