Transient Diffusive Interactions with a Protein Crowder Affect Aggregation Processes of Superoxide Dismutase 1 β-Barrel
Transient Diffusive Interactions with a Protein Crowder Affect Aggregation Processes of Superoxide Dismutase 1 β-Barrel
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DOI：
10.1021/acs.jpcb.0c11162
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发表时间：
2021-03-03
影响因子：
3.3
通讯作者：
Sugase, Kenji
中科院分区：
文献类型：
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作者：
Iwakawa, Naoto;Morimoto, Daichi;Sugase, Kenji
运动神经元内超氧化物歧化酶1（SOD 1）的聚集形成被认为是肌萎缩侧索硬化症发病的主要因素。SOD1 β桶的热力学稳定性已被证明在拥挤的环境中（如细胞内）会降低，但目前仍不清楚拥挤诱导的蛋白质不稳定的热力学如何与SOD1聚集相关。在这里，我们研究了蛋白质拥挤，溶菌酶，对原纤维聚集体形成的SOD 1 β桶的影响。我们发现，即使在轻度拥挤的解决方案中，聚集体形成的SOD 1减速。有趣的是，与溶菌酶的瞬时扩散相互作用不会显著影响SOD 1 β桶的静态结构，但稳定了另一种激发的“不可见”状态。拥挤的净效应是有利于物种的聚集途径，从而解释了在拥挤的环境中的减速聚集。我们的观察结果表明，细胞内环境可能有一个类似的负面（抑制）的影响，在活细胞中的其他淀粉样蛋白原纤维的形成。破译拥挤的细胞内环境如何影响聚集和原纤维形成的疾病相关蛋白质可能会成为核心，在理解这些神秘的疾病的病因聚集的确切作用。
Aggregate formation of superoxide dismutase 1 (SOD1) inside motor neurons is known as a major factor in onset of amyotrophic lateral sclerosis. The thermodynamic stability of the SOD1 beta-barrel has been shown to decrease in crowded environments such as inside a cell, but it remains unclear how the thermodynamics of crowding-induced protein destabilization relate to SOD1 aggregation. Here we have examined the effects of a protein crowder, lysozyme, on fibril aggregate formation of the SOD1 beta-barrel. We found that aggregate formation of SOD1 is decelerated even in mildly crowded solutions. Intriguingly, transient diffusive interactions with lysozyme do not significantly affect the static structure of the SOD1 beta-barrel but stabilize an alternative excited "invisible" state. The net effect of crowding is to favor species off the aggregation pathway, thereby explaining the decelerated aggregation in the crowded environment. Our observations suggest that the intracellular environment may have a similar negative (inhibitory) effect on fibril formation of other amyloidogenic proteins in living cells. Deciphering how crowded intracellular environments affect aggregation and fibril formation of such disease-associated proteins will probably become central in understanding the exact role of aggregation in the etiology of these enigmatic diseases.