PDF(Pubmed)
Abstract：
Phosphorylation plays a crucial role in the regulation of many fundamental cellular processes. Phosphorylation levels are increased in many cancer cells where they may promote changes in mitochondrial homeostasis. Proteomic studies on various types of cancer identified 17 phosphorylation sites within the human ATP-dependent protease Lon, which degrades misfolded, unassembled and oxidatively damaged proteins in mitochondria. Most of these sites were found in Lon\'s N-terminal (NTD) and ATPase domains, though little is known about the effects on their function. By combining the biochemical and cryo-electron microscopy studies, we show the effect of Tyr186 and Tyr394 phosphorylations in Lon\'s NTD, which greatly reduce all Lon activities without affecting its ability to bind substrates or perturbing its tertiary structure. A substantial reduction in Lon\'s activities is also observed in the presence of polyphosphate, whose amount significantly increases in cancer cells. Our study thus provides an insight into the possible fine-tuning of Lon activities in human diseases, which highlights Lon\'s importance in maintaining proteostasis in mitochondria.
摘要：
磷酸化在许多基本细胞过程的调节中起着至关重要的作用。磷酸化水平在许多癌细胞中增加,其中它们可以促进线粒体稳态的改变。对各种类型癌症的蛋白质组学研究确定了人ATP依赖性蛋白酶Lon中的17个磷酸化位点，它降解了错误折叠，线粒体中未组装和氧化损伤的蛋白质。这些位点大部分位于Lon的N端（NTD）和ATP酶结构域，尽管对其功能的影响知之甚少。通过结合生化和低温电子显微镜研究，我们显示了Tyr186和Tyr394磷酸化在Lon的NTD中的作用，大大降低了所有Lon活性，而不会影响其结合底物或干扰其三级结构的能力。在多磷酸盐的存在下，也观察到Lon的活性大幅降低，其数量在癌细胞中显著增加。因此，我们的研究提供了对人类疾病中Lon活动可能进行微调的见解，这凸显了Lon在维持线粒体蛋白质稳定方面的重要性。
