Lucato Christina M, Lupton Christopher J, Halls Michelle L, Ellisdon Andrew M
Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
J Mol Biol. 2017 May 5;429(9):1289-1304. doi: 10.1016/j.jmb.2017.03.021. Epub 2017 Mar 22.
The misfolding of proteins to form amyloid is a key pathological feature of several progressive, and currently incurable, diseases. A mechanistic understanding of the pathway from soluble, native protein to insoluble amyloid is crucial for therapeutic design, and recent efforts have helped to elucidate the key molecular events that trigger protein misfolding. Generally, either global or local structural perturbations occur early in amyloidogenesis to expose aggregation-prone regions of the protein that can then self-associate to form toxic oligomers. Surprisingly, these initiating structural changes are often caused or influenced by protein regions distal to the classically amyloidogenic sequences. Understanding the importance of these distal regions in the pathogenic process has highlighted many remaining knowledge gaps regarding the precise molecular events that occur in classic aggregation pathways. In this review, we discuss how these distal regions can influence aggregation in disease and the recent technical and conceptual advances that have allowed this insight.
蛋白质错误折叠形成淀粉样蛋白是几种进行性且目前无法治愈的疾病的关键病理特征。从机制上理解从可溶性天然蛋白质到不溶性淀粉样蛋白的途径对于治疗设计至关重要，最近的研究有助于阐明引发蛋白质错误折叠的关键分子事件。一般来说，在淀粉样蛋白生成早期会发生整体或局部结构扰动，从而暴露出蛋白质易于聚集的区域，这些区域随后可自我缔合形成有毒的寡聚体。令人惊讶的是，这些引发结构变化通常是由经典淀粉样蛋白生成序列远端的蛋白质区域引起或影响的。了解这些远端区域在致病过程中的重要性凸显了经典聚集途径中发生的精确分子事件方面仍存在的许多知识空白。在这篇综述中，我们讨论了这些远端区域如何影响疾病中的聚集以及促成这种见解的最新技术和概念进展。
