Extraction and Refolding Determinants of Chaperone-Driven Aggregated Protein Reactivation.,Journal of Molecular Biology

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Extraction and Refolding Determinants of Chaperone-Driven Aggregated Protein Reactivation.
Journal of Molecular Biology ( IF 4.7 ) Pub Date : 2020-03-05 , DOI: 10.1016/j.jmb.2020.03.002
José Angel Fernández-Higuero ₁ , Arturo Muga ₁ , Jose M G Vilar ₂

Affiliation

Reactivation of protein aggregates plays a fundamental role in numerous situations, including essential cellular processes, hematological and neurological disorders, and biotechnological applications. The molecular details of the chaperone systems involved are known to a great extent but how the overall reactivation process is achieved has remained unclear. Here, we quantified reactivation over time through a predictive mechanistic model and identified the key parameters that control the overall dynamics. We performed new targeted experiments and analyzed classical data, covering multiple types of non-ordered aggregates, chaperone combinations, and experimental conditions. We found that, irrespective of the behavior observed, the balance of surface disaggregation and refolding in solution universally determines the reactivation dynamics, which is broadly described by two characteristic times. This characterization makes it possible to use activity measurements to accurately infer the underlying loss of aggregated protein and to quantify, for the first time, the refolding rates of the soluble intermediates.

中文翻译：

伴侣驱动的聚集蛋白活化的提取和重折叠决定因素。

蛋白质聚集体的再激活在许多情况下都起着基本作用，包括必要的细胞过程，血液和神经系统疾病以及生物技术应用。所涉及的分子伴侣系统的分子细节在很大程度上是已知的，但是如何实现整个再活化过程仍不清楚。在这里，我们通过预测性机理模型对随时间的重新激活进行了量化，并确定了控制总体动力学的关键参数。我们进行了新的针对性实验并分析了经典数据，涵盖了多种类型的无序聚集体，分子伴侣组合和实验条件。我们发现，不管观察到的行为如何，溶液中表面分解和重新折叠的平衡都决定了重新活化的动力学，大致用两个特征时间来描述。这种表征使得可以使用活性测量准确地推断出聚集蛋白的潜在损失，并首次量化可溶性中间体的重折叠速率。

更新日期：2020-03-05

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