过饱和是神经退行性疾病中蛋白质聚集的主要驱动力。
Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases.
作者信息
Ciryam Prajwal, Kundra Rishika, Morimoto Richard I, Dobson Christopher M, Vendruscolo Michele
机构信息
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK; Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
出版信息
Trends Pharmacol Sci. 2015 Feb;36(2):72-7. doi: 10.1016/j.tips.2014.12.004. Epub 2015 Jan 27.
The solubility of proteins is an essential requirement for their function. Nevertheless, these ubiquitous molecules can undergo aberrant aggregation when the protein homeostasis system becomes impaired. Here we ask: what are the driving forces for protein aggregation in the cellular environment? Emerging evidence suggests that this phenomenon arises at least in part because the native states of many proteins are inherently metastable when their cellular concentrations exceed their critical values. Such 'supersaturated' proteins, which form a 'metastable subproteome', are strongly driven towards aggregation, and are over-represented in specific biochemical pathways associated with neurodegenerative conditions. These observations suggest that effective therapeutic approaches designed to combat neurodegenerative diseases could be aimed at enhancing the ability of the cell to maintain the homeostasis of the metastable subproteome.
蛋白质的溶解性是其发挥功能的基本要求。然而，当蛋白质稳态系统受损时，这些普遍存在的分子会发生异常聚集。在此我们提出疑问：细胞环境中蛋白质聚集的驱动力是什么？新出现的证据表明，这种现象至少部分是因为当许多蛋白质的细胞浓度超过其临界值时，它们的天然状态本质上是亚稳态的。这些形成“亚稳态亚蛋白质组”的“过饱和”蛋白质会被强烈驱动发生聚集，并且在与神经退行性疾病相关的特定生化途径中过度存在。这些观察结果表明，旨在对抗神经退行性疾病的有效治疗方法可能旨在增强细胞维持亚稳态亚蛋白质组稳态的能力。
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