Cellular strategies for regulating functional and nonfunctional protein aggregation.
Cellular strategies for regulating functional and nonfunctional protein aggregation.
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DOI：
10.1016/j.celrep.2012.09.036
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发表时间：
2012-11-29
期刊：
影响因子：
8.8
通讯作者：
Babu MM
中科院分区：
文献类型：
--
作者：
Gsponer J;Babu MM
越来越多的证据表明，易于聚集的蛋白质对细胞既有害又具有功能。细胞系统如何平衡蛋白质聚集的有害和有益影响？我们发现，与非聚集倾向的蛋白质相比，聚集倾向的蛋白质受到差异化的转录、翻译和降解控制，这导致它们的合成减少、丰度低和周转率高。增强聚集表型的遗传调节剂富含影响表达稳态的基因。此外，编码易聚集蛋白的基因在过度表达时更可能有害。这些趋势在进化上是保守的，并提出了一种策略，即细胞机制专门调节易于聚集的蛋白质的可用性，以（1）将浓度保持在聚集所需的临界浓度以下，以及（2）改变单体和寡聚/聚集形式之间的平衡，正如勒夏特列原理所解释的那样。该策略可以防止不需要的聚集体的形成并保持功能性组装体/聚集体处于控制之下。 ► 编码易聚集蛋白的 mRNA 很复杂，表明翻译调控能力更强 ► 易聚集蛋白的存在丰度较低且持续时间较短 ► 严格控制在进化上是保守的，并且具有抗聚集的鲁棒性 ► 易聚集蛋白受到严格调控 虽然蛋白质聚集体的沉积是各种神经退行性疾病的标志，但最近的研究表明，蛋白质 聚集在不同的生理过程中被利用。这些观察结果提出了细胞如何平衡聚集的有害和有益影响的问题。 Gsponer 和 Babu 揭示，与非聚集倾向的蛋白质相比，倾向聚集的结构化和无序蛋白质受到不同的调节。他们的结果为理解细胞中功能性和非功能性蛋白质聚集的控制提供了一个统一的框架。
Growing evidence suggests that aggregation-prone proteins are both harmful and functional for a cell. How do cellular systems balance the detrimental and beneficial effect of protein aggregation? We reveal that aggregation-prone proteins are subject to differential transcriptional, translational, and degradation control compared to nonaggregation-prone proteins, which leads to their decreased synthesis, low abundance, and high turnover. Genetic modulators that enhance the aggregation phenotype are enriched in genes that influence expression homeostasis. Moreover, genes encoding aggregation-prone proteins are more likely to be harmful when overexpressed. The trends are evolutionarily conserved and suggest a strategy whereby cellular mechanisms specifically modulate the availability of aggregation-prone proteins to (1) keep concentrations below the critical ones required for aggregation and (2) shift the equilibrium between the monomeric and oligomeric/aggregate form, as explained by Le Chatelier’s principle. This strategy may prevent formation of undesirable aggregates and keep functional assemblies/aggregates under control. ► mRNA encoding aggregation-prone proteins is complex, suggesting greater translational regulation ► Aggregation-prone proteins are present in low abundance and for short periods of time ► Tight control is evolutionarily conserved and provides robustness against aggregation ► Aggregation-prone proteins are subject to tight regulation Although deposits of protein aggregates are the hallmark of various neurodegenerative diseases, recent studies have demonstrated that protein aggregation is exploited in different physiological processes. These observations raise the question of how cells balance the detrimental and beneficial effects of aggregation. Gsponer and Babu reveal that aggregation-prone structured and disordered proteins are subject to differential regulation compared to non-aggregation-prone proteins. Their results provide a unifying framework for understanding the control of functional and nonfunctional protein aggregation in cells.
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